1,2,3,4-tetrahydrobenzol(b)(1,6)naphthyridine derivatives

ABSTRACT

THIS INVENTION CONCERNS 1,2,3,4-TETRAHYDROBENZO(B) (1,6)NAPHTHYRIDINE, 1,2,3,4,4A,5,10,10A-OCTAHYDROBENZO (B)(1,6)NAPHTHYRIDINES AND THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF WHICH ARE PHARMACOLOGICALLY ACTIVE AS CENTRAL NERVOUS SYSTEM DEPRESSANTS WHICH ARE USEFUL IN PRODUCING A CALMING EFFECT IN WARMBLOODED ANIMALS. FURTHER, THIS INVENTION CONCERNS A PROCESS FOR THE PREPARATION OF 10-AMINO-1,2,3,4-TETRAHYDROBENZO(B)(1,6)NAPHTHYRIDINES.

United States Patent Office US. Cl. 260-286 6 Claims ABSTRACT OF THE DISCLOSURE This invention concerns 1,2,3,4 tetrahydrobenzo[b] [1,6]naphthyridine, 1,2,3,4,4a,5,10,10a octahydrobenzo [b] [l,6]naphthyridines and the pharmacologically acceptable acid addition salts thereof which are pharmacologically active as central nervous system depressants which are useful in producing a calming effect in warmblooded animals. Further, this invention concerns a process for the preparation of 10 amino 1,2,3,4 tetrahydrobenzo [b] [1,6] naphthyridines.

This application is a continuation-in-part of United States Patent applications: Ser. No. 533,802, entitled l-Aminobenzo[b][1,6]Naphthyridines, filed on Mar. 14, 1966 by Milton Wolf; Ser. No. 533,793, entitled 1,2,3,4 Tetrahydrobenzo[b][1,'6]Naphthyridine Derivatives, filed on Mar. 14, 1966 by Milton Wolf and James L. Diebold; and Ser. No. 581,756, entitled 1,2,3,4-Tetrahydrobenzo[b][1,6]Naphthyridine Derivatives, filed Sept. 22, 1966 by Milton Wolf and James L. Diebold, all now abandoned.

This invention is directed to novel compounds classified in the art of organic chemistry as benzonaphthyridines and to a process for making some of these compounds. More particularly, the present invention is concerned with 1,2,3,4 tetrahydrobenzo[b] [1,6]naphthyridines and 1,2, 3,4,4a,5,10,10a octahydrobenzo[b] [1,6]naphthyridine derivatives which in standard and accepted pharmacological tests have demonstrated central nervous system depressant activity which is useful in producing a calming effect in warm-blooded animals.

In its composition aspect, the claimed invention resides in a composition of matter having a tetrahydro or a octahydrobenzo[b][l, 6]naphthyridine substituted nucleus. These compounds are exemplified by the following formulae:

i o 4 2 l a R R A NR(l NR3 1 and 1 A} R R 111 N 111 III 5 wherein R and R are selected from the group consisting of hydrogen, halogen, nitro, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, carbamoyl, sulfamoyl, and trifluoromethyl; R is selected from the group consisting of hydrazine, amino, aminoanilino, anilino, di (lower) alkylamino (lower) alkylamino, amino (lower) alkylthio, phenyl, sulfamylphenyl, carboxyphenyl, phenylhydrazino, halophenyl, lower alkylphenyl, lower alkoxyphenyl, lower alkylthiophenyl, phenoxy, phenthio, morpholino, pyridyl, thienyl, and furyl, 4-alkyl-1-piperazinyl; and B is selected from the group consisting of hydrogen, amidino, lower alkyl, di(lower)alkyl, phenyl, lower alkyl- 3,580,915 Patented May 25, 1971 phenyl, halophenyl, phen(l0wer) alkyl, benzoyl, lower alkanoyl, halo (lower) alkanoyl, dihalo (lower) alkanoyl, lower alkanoyloxy, di(lower)alkylaminoflower)alkanoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylcarbamoyl, lower alkoxy (lower) alkyl, di(lower) alkylamino (lower) alkyl, dihydroxy(lower)alkyl and 5,5-dimethyl-3-oxo-lcyclohexen-l-yl; R and R when taken separately are both selected from the group consisting of hydrogen, dimethyl, lower alkyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl and phen(lower)alkyl, and when R, and R are concatenated they form an ethano bridge; and the pharmacologically acceptable acid addition salts thereof. As employed herein the terms lower alkyl, lower alkoxy, lower alkanoyl and the like are meant to include both branched and straight chain hydrocarbon moieties having from about one to about six carbon atoms.

The compounds of the present invention possess the inherent physical properties of being relatively high melting yellowish to colorless solids, and substantially insoluble in water. Examination of these compounds produced by the hereinafter described processes reveals data confirming the molecular structures hereinbefore set forth. The aforementioned physical characteristics, taken together with the nature of the starting materials and the mode of synthesis positively confirm the structure of the compounds of this invention.

The new and novel compounds of the above formula (I) properly are called tetrahydrobenzonaphthyridines, Typical examples therof are: 8-chloro-1,2,3,4-tetrahydro- 2-methyl-10-phenylbenzo[b][1,6]naphthyridine and 2- benzyl-8-chloro-l,2,3,4-tetrahydro 10 phenylbenzo[b] [1,6]naphthyridine. The compounds of the present invention of Formula I wherein R is amino, aminoanilino, anilino, hydrazino and phenylhydrazino may exist in two forms, as shown in the following tautomeric structures,

wherein R, R, R R and R are defined as above; and R is selected from the group consisting of hydrogen, aminophenyl, phenyl, amino and phenylamino. For the purpose of simplicity these tautomers (a) and (b) shall hereinafter be designated and named as the 10-position amino compounds of formula (a), for example: IO-amino-1,2,3,4-tetrahydro-2-methylbenzo [b] [1,6]naphthyridine; 10- (o-aminoanilino -7-chloro-l,2,3,4-tetrahydro 2- methylbenzo[b] [1,6] naphthyridine; 10-anilino-8-chloro-1 ,2, 3 ,4-tetr ahydro-Z-methylbenzo [b] [1,6] naphthyridine; (8-chloro-l,2,3 ,4-tetrahydro-2-methy1benzo [b] 1,6]

naphthyridin-lO-yl)hydrazine; and l-(7-chloro-1,2,3,4-tetrahydro-2-methylbenzo [b] [1,6

naphthyridin-lO-yl)-2-phenylhydrazine.

It should be understood, however, that the present invention also encompasses and includes the corresponding 10- position imino compounds of formula (b). When the compounds of this invention are represented by the Formula II they are designated octahydrobenzonaphthyridiness," such as 2-benzyl-8-chloro-1,2,3,4,4a,5,10,10a-octahydrobenzonaphthyridine and 8-chloro-1,2,3,4,4a,5,10,10a-octahydro-Z-methyl-10-phenylbenzo [b] 1,6] naphthyridine.

Some of the tetrahydrobenzonaphthyridine of the present invention may be prepared by the interaction of a o-aminocarbonyl compound with a 4-piperidone. The first process is further elucidated in the following reaction scheme:

\ C=O N-Ri Condent NH2 sation R w A y 5 N ridyl, thienyl, and furyl. This reaction is conducted in the presence of a strong acid at a temperature from about 70 C. to about 210 C. for a period of about fifteen minutes to about four hours. Preferably, this reaction is conducted in polyphosphoric or trifluoroacetic acid. When the reaction is complete, the reaction mixture is cooled and then admixed with an ice-water mixture. The resulting solution is then filtered and made basic to separate the appropriate tetrahydrobenzonaphthyridine.

Alternatively, the above-defined tetrahydrobenzonapththyridines may be prepared by heating the reactants to fusion with the passage of hydrogen chloride gas through the melt. This operation results in an exothermic reaction accompanied by the evolution of water. To complete the reaction the reaction mixture is again heated up to about 200-210" C. The reaction mixture is then cooled, triturated with an alkanol and the product recovered as the hydrochloride salt by conventional means.

In accord with the new and novel process of the present invention, the 10-aminotetrahydrobenzonaphthyridines of this invention may be prepared by the reaction of a 2- aminobenzonitrile with an appropriate 4-piperidone. This second process is exemplified by the following reaction scheme:

wherein R, R R R and R are defined as above. The reaction is effected by heating a substantially equimolar mixture of the reactants, in the presence of a strong acid, at a temperature from about 140 C. to about 200 C. for a period of from about one-half hour to two hours. Preferably, this reaction is conducted in polyphosphoric acid at about 150 C. for about one hour. By strong acid as employed in these first two processes is meant any organic or inorganic acid which dissolves the reactants and does not interfere with their interaction. Although many such acids may be employed, as will suggest themselves to those skilled in the art, excellent results have been obtained with polyphosphoric, trifluoroacetic, acetic and alkanesulfonic and arylsulfonic acids, for example, benzenesulfonic, and toluenesulfonic acid, methylsulfonic acid and ethylsulfonic acid.

After the reaction is complete, the reaction mixture is cooled and basified with an aqueous alkaline solution, for example, sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate. Thereafter, the 10- aminotetrahydrobenzonaphthyridine is obtained by conventional methods such as filtration and crystallization from a suitable solvent.

4 The other tetrahydrobenzonaphthyridines of this invention may be prepared by a third process which is depicted by the following reaction scheme:

R4 OH wherein R, R R R and R are defined as above, and R is is selected from the group consisting of aminoanilino, anilino, di(lower)alkylamino(lower)alkylamino, phenoxy, morpholino, 4-alkyl-l-piperazinyl, phenthio, amino(lower)alkylthio, hydrazino and phenylhydrazino. The l0-chlorotetrahydronaphthyridine intermediates are prepared by the interaction of an anthranilic acid, an appropriate 4-piperidone and phosphorus oxychloride at about the reflux temperature of the reaction mixture for a period of about one to about four hours. The reaction mixture is then evaporated, the residue dissolved in a water-immiscible organic solvent, e.g. methylene chloride which is then added to a cold aqueous alkaline solution, e.g. ammonium hydroxide. Thereafter the l0-chlorotetrahydrobenzonaphthyridine intermediate is separated by standard procedures, e.g. the water layer is washed, dried and evaporated to aflord the intermediate which may be further purified by crystallization from a suitable solvent, e.g. a liquid alkane.

The tetrahydrobenzonaphthyridine of this invention wherein R is aminoanilino, anilino, di(lower)alkylamino- (lower)alkylamino, phenoxy, morpholino and 4-alkyl-lpiperazinyl are prepared by the condensation of an above prepared l0-chloro-tetrahydrobenzonaphthyridine intermediate with an appropriate proton donor reactant, e.g. aminoaniline, aniline, a di(lower)alkylamino(lower)- alkylamine; phenol and morpholine. The reaction is effected by admixing a l0-chlorotetrahydrobenzonaphthyridine with phenol and heating the resulting mixture, under an inert atmosphere e.g. nitrogen, to about C. for a period of about fifteen to about thirty minutes. Thereafter, the proton donor reactant is slowly added and the reaction mixture is then heated to about reflux temperatures for a period of about five to about eight hours. When the reaction is complete, the resulting product is recovered by standard procedures, e.g., the product is dissolved in a water-immiscible organic solvent e.g. methylene chloride, extracted with an aqueous alkali metal hydroxide solution, dried, evaporated to dryness and the residue is then recrystallized from a suitable solvent e.g. benzene.

The tetrahydrobenzonaphthyridines of this invention wherein R is arylthio and alkylthio, e.g. phenthio and amino(lower)alkylthio are prepared by the condensation of an above-prepared lO-chlorotetrahydrobenzonaphthyridine with an appropriate mercaptan reactant, e.g. phenyl mercaptan and an amino(lower)alkyl mercaptan. The reaction is effected by admixing a 10-chlorotetrahydrobenzonaphthyridine, an appropriate mercaptan, and from about one to about two molar excess of an aqueous alkali metal hydroxide solution in an alkanol and then heating the resulting mixture to about reflux temperatures for a period of about one to about three hours. When the reaction is complete, the product, a 10-thiotetrahydrobenzonaphthyridine, is separated by conventional recovery methods. For example, the reaction mixture is evaporated to dryness, the residue dissolved in a water-immiscible organic solvent, e.g. methylene chloride, this organic layer is then evaporated to dryness and the residue is recrystallized from an appropriate solvent e.g. hexane. The

-arylthiotetrahydronaphthyridines may also be prepared by the condensation reaction described in hereinafter Example LVIII.

The tetrahydrobenzonaphthyridines of this invention wherein R is hydrazino and phenylhydrazino are prepared by the condensation of an above prepared 10-chlorotetrahydrobenzonaphthyridine with an appropriate hydrazine this reaction is conducted in an alkanol at about reflux temperatures for a period of about one to about eight hours. Thereafter, the resulting product, a tetrahydrobenzonaphthyridinyl hydrazine, is separated by standard procedures, as exemplified in hereinafter Examples LX-LXI.

The above-described 2-lower alkanolyloxy tetrahydrobenzonaphthyridines, the 2-halo(lower)alkanoyl tetrahydrobenzonaphthyridines, the Z-amidino tetrahydrobenzonaphthyridines, the 2-dihydroxy(lower)alkyl tetrahydrobenzonaphthyridines, the 2-di(lower)alkylaminoflower) alkanoyl tetrahydrobenzonaphthyridines, and the Z-dihalo (lower)alkanoyl tetrahydrobenzonaphthyridines may also be prepared by the procedures described in detail in the herinafter listed Examples XIX to XXV.

The octahydrobenzonaphthyridine compounds of the present invention are prepared by the hydrogenation of their corresponding above prepared tetrahydrobenzonaphthyridine, as exemplified by the following reaction:

wherein R, R R R R and R are defined as above. Although various reduction procedures maybe employed, a preferred method to effect this conversion 1s the use of a reducing agent such as hydrogen gas. Utilizing this preferred method, a tetrahydrobenzonaphthyridine is admixed with glacial acetic acid and platinum oxide at about 30 C., under a hydrogen pressure of about 50 psi, for a period of about twenty-four hours. Thereafter, the product is separated by evaporation of the excess acetic acid and the residue is dissolved in water, basified and recrystallized to yield the appropriate octahydrobenzonaphthyridlne.

As is evident from the above-described methods of producing the tetrahydrobenzonaphthyridine and octahydrobenzonaphthyridine compounds of this invention, these compounds can be recovered either in the form of then acid addition salts or as the free bases. These tetrahydrobenzonaphthyridine and octahydrobenzonaphthyridine bases can be converted to their acid addition salts by reacting them with the usual acids, e.g. hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric or with an organic acid, for example, citric, acetic, benzoic, methanesulfonic or p-toluenesulfonic. While the free bases have the same pharmacological properties as their acid addition salts, they are more often utilized in the preparation of such salts rather than directly for their pharmacological effects.

In accord with the present invention, the new and novel tetrahydrobenzonaphthyridine and octahydrobenzonaphthyridine compounds of this invention have been found to possess interesting pharmacological properties. More particularly, these compounds, in standard pharmocological tests, have exhibited utility as central nervous system depressants which are useful in producing a calming eifect, particularly in laboratory and domestic animals.

In the pharmacological evaluation of the central nervous system depressant compounds of this invention the in vivo effects of the compounds of this invention are tested as follows:

The compound is administered orally as a 1% suspension emulsified with polyethylene oxide sorbitan monooleate to three mice (14 to 24 grams) at each of the following doses: 400, 127, 40, 12.7 and 4.0 mg./kg. The animals are watched for a minimum of two hours during which time signs of general stimulation (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration) and autonomic activity (i.e., miosis, mydriasis, diarrhea) are noted. The animals are tested for changes in reflexes (i.e., flexor, extensor) and are rated for their Sedative-Ataxic Score by use of a pole climb and inclined screen for the presence of sedation-ataxia [Kouzmanoff et al., J. Pharm. Exp. Ther. 144, 40A (1958)]. The Eddy Hot-Plate Method [Nathan B. Eddy and Dorothy Leimbach, Jr. Pharmacol. Exper. Therap., 107, 385 (1953)] is used to test for analgesia. The experiment is terminated by subjecting each animal to a maximal electroshock to test for anticonvulsant activity.

The tetrahydrobenzonaphthyridine and octahydrobenzonaphthyridine compound of this invention in the above test procedure produce decreased motor activity when administered at a dosage range from 12.7 to 400 mg./kg.; produce decreased respiration when administered at a dosage range from 40 to 400 mg./kg. and rate a sedativeataxic score of 1-2 when administered at a dosage range from 40 to 400 mg./kg. There were no deaths at the highest dose used, 400 mg./kg.

When the tetrahydrobenzonaphthyridine and octahydrobenzonaphthyridine compounds of this invention are employed as central nervous system depressants to produce a calming effect in warm-blooded animals, e.g., mice, rats, rabbits, dogs, cats, monkeys, etc. they may be administered alone or in combination with pharrnacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compounds, chosen route of administration and standard biological practice. For example, they may be administered orally in the form containing such excipients as starch, milk sugar and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present tetrahydrobenzonaphthyridines and octahydrobenzonaphthyridines compounds when employed as central nervous system depressant agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

Further, it has been surprisingly found that 8-chloro- 1,2,3,4 tetrahydro 1,1,3,3 tetramethyl IO-phenylbenzo[b][1,6]naphthyridine and 8-chloro-1,2,3,4-tetrahydro- 10-phenylbenzo[b][l,6]naphthyridine of the present invention also possess valuable amebicidal activity. In particular, when tested in standard in vitro screening procedures these two compounds have demonstrated anti-ameblC activity, especially against Endameba histolytica and are, therefore, useful as anti-amebic agents.

In the amebicidal evaluation of these two compounds of this invention, the test compound is incorporated and diluted in the aqueous phase of Boeck-Drbohlav diphasic medium fortified With rice starch. The medium is inoculated with polybacteria and a known number of trophozoites of E. histolytica NIH 200. After forty-eight hours incubation at 35 C., the trophozoites are counted. The procedure is derived from Thompson, et al., Antibo. and Chemo, 6, 337-50 (1956). The endpoint is expressed as the percent of E. histolytica killed at a particular concentration (pg/ml.) of test compound. In this test, S-chloro- 1,2,3,4 tetrahydro 1,1,3,3 tetramethyl 10 phenylbenzo[b][1,61naphthyridine averaged about a percent kill of E. histolytica at a concentration of g/ml. and 8- chloro 1,2,3,4 tetrahydro 10 phenylbenzo[b] [1,6] naphthyridine averaged about a 100 percent kill of E. histolytz'ca at a concentration of about ,ug/ml.

The anti-amebic activity of these two compounds of this invention can be utilized for washing equipment in hospitals and homes, instruments used in medicine and bacteriology, clothing used in bacteriological laboratories, and floors, walls and ceiling in rooms in which a background free of E. histolytica is desired.

Still further, it has been unexpectedly found that 8-chloro-1,2,3 ,4-tetrahydro-1,1,3 ,3-tetrahydromethyllO-phenylbenzo [b] [1,6] naphthyridine; 8-chloro-1,2,3 ,4-tetrahydro-2phenethyl-10-phenylbenzo [b] 1,6] naphthyridine; 8-chloro-1,2,3,4-tetrahydro-2-methyl-10-phenyl-1,3-

ethanobenzo [b] [1,6] naphthridine; 1,2,3,4-tetrahydro-1,1,3 ,3 -tetramethyl--(p-tolyl) benzo [b] [1,6] naphthyridine; 6-chloro-1,2,3,4-tetrahydro-1,1,3 ,3-tetramethyl-10- phenylbenzo [b] [1,6] naphthyridine; 7-chloro-1,2,3 ,4-tetrahydro-1,1,3 ,3-tetramethyl-10- (p-methylthiophenyl) benzo [b] [1,6 naphthyridine; 7,8-dimethoxy-l ,2,3,4-tetrahydro-1,1,3 3-tetramethyl-10- (p-methoxyphenyl)benzol [b] 1,6]naphthyridine; 8-chloro-2-chloroacetyl-1,2,3 ,4-tetrahydro-10-phenylbenzo [b] [1,6] naphthyridine; 2-amidino-8-chloro-1,2,3 ,4-tetrahydro-10-phenylbenzo [b] [1,6 naphthyridine; m-(2 benzyl-8-chloro-1,2,3 ,4-tetrahydro-10-benzo [b] [1,6] naphthyridinyl benzenesulfonarnide; 2-benZyl-6-chloro-1,2,3,4-tetrahydro-10-phenylbenzo [1)] [1,6] naphthyridine; 2-benzyl-7-chloro- 1,2,3 ,4-tetrahydro-10-phenylbenzo [b] [1,6]naphthyn'dine; 10-anilino-7-chloro-1,2,3,4-tetrahydro-2-methylbenzo [b] [1,6] naphthyridine; 7-chloro-1,2,3,4-tetrahydro-2-methyl-10-(phenylthio) benzo [b] [1,6] naphthyridine; 1-(7-chloro-1,2,3 ,4-tetrahydro-2-methy1benzo b] 1,6]

naphthyridin-l O-yl -2-phenylhydrazine; 10-anilino-8-chloro-1,2,3 ,4-tetrahydro-2-methylbenz o[b] [1,6]naphthyridine; and 3-( 8-ch1oro-1,2,3 ,4-tetrahydro- 1 O-phenylbenzo [b] [1,6] naphthyridin-Z-yl -5,5-dimethyl-2-cyclohexenl-one also possess valuable anti-bacterial properties. More par ticularly, these seventeen compounds, when tested in standard bacteriological procedures have exhibited utility as antibacterial compounds, especially as antitubercular agents.

The invitro bacteriocidal activity of these seventeen compounds of this invention against tubercle bacilli is tested by the following procedure:

A stock solution containing 1000 ,ug./ml. of a test compound in a suitable vehicle e.g. water is prepared. One ml. quantities of various dilutions of this stock solution are added to individual tubes containing 9 ml. of 'medium to give final concentrations within the range of 0.01 to 100 ,ug./ml. These tubes are then seeded with 0.1 ml. of standardized bacterial suspension and incubated for two weeks at 37 C. The media employed in Dubos Oleic acid liquid medium and the stock cultures are maintained on Dorset Egg Agar. The organisms used are M. tuberculosis, human type, strain H 37 Rv and M. tuberculosis, bovine type, strain Rabenel. The results are expressed as minimal inhibitory concentration (MIC) in ugJml. which is the least concentration of a compound that will completely prevent the growth of the organism. In the above test, these seventeen tetrahydrobenzonaphthyridine compounds of this invention completely inhibit the growth of tubercle bacilli at a MIC in the range of about 0.5 to about 50 ng/ ml.

As has been mentioned hereinabove, these latter seventeen tetrahydrobenzonaphthyridine compounds of this invention are also biocidally active, as antibacterial agents. In this connection, they exhibit activity against pathogenic bacteria, specifically in vitro antitubular activity as bacteriocidal agents against tubercle bacteria. Their bacteriocidal properties make these seventeen compounds valuable in biocidal compositions in a variety of important fields for use. For example, they can be formulated and used in bacteriocidally active institutional cleaning compositions, and in soaps and detergents. These compositions are employed for washing equipment in hospitals and homes, instruments used in medicine and bacteriology, clothing used in bacteriological laboratories, and floors, walls and ceiling in rooms in which a background free of tubercle bacteria is desired. When either the two abovedescribed anti-amebic agents or the seventeen aforesaid anti tubercular agents are used for their biocidal purposes, they are applied according to their desired end-uses as powders, solutions, suspensions and the like, containing the active substance generally in concentrations of 0.1% to 0.7% by weight, or even as much as 1%, 1.5%, 1.8%, 2% and up to about 5%. In washing solutions, e.g. for hospitals and homes, the active antiamebic and antitubercular compounds of this invention will be used generally in the range of from about 0.02% to .25 by weight.

Although, in common with most organic substances, with relatively high molecular weights, the antiamebic and anti-tubercular compounds of this invention have limited solubility in water, those skilled in the art will have no great difliculty in formulating them into a wide variety of biocidally-active compositions. In general, standard techniques can be employed and, where necessary, advantage is taken of the ability of these compounds to form salts with acids, which have enhanced solubility in water. The active compounds per se can be made up in dilute aqueous solution. They can also be formulated as suspensions or solutions in an aqueous vehicle containing an organic co-solvent, such as, for example, an alkanol. Also, aqueous vehicles containing emulsifying agents, such as sodium lauryl sulfate, and relatively high concentrations, e.g., up to about 5% by weight, of the compounds of this invention can be formulated by conventional technlques;

The reactants employed in the first three abovedescribed processes are known compounds which are commercially available and/or prepared by well known procedures. In this regard, the 4-piperidone reactants may be prepared by the methods described in S. M. McElvain and K. -Rorig in J. Am. Chem. Soc. 7 0, 1829 (1948); S. M. McElvain in J. Am. Chem. Soc. 46, 1725 (1924); S. M. McElvain in J. Am. Chem. Soc. 48, 2179 (1926); S. M. McElvain and G. Stork in J. Am. Chem. Soc. 68, 1049 (1946); I. R. Thayer and S. M. McElvain in I. Am. Chem. Soc. 49, 2862 (1927); J. B. Baty, G. Jones and C. Moore in J. C. pg. 2645 (1967); and J. Guareschi, Ber. 28, 1960 (1895).

The o-aminocarbonyl compound reactants employed in the first above-described process may be prepared by the procedures described by: G. N. Walker in J. Org. Chem. 27, 1929 (1962); F. Korte and O. Behner in Ann. 6 21, 51 (1959); S. Bell et al., in US. Pat. No. 3,516,992 of June 9, 1970 entitled 3-(2-Amino-5-Halo, 5-Alkyl-and-5-Alkoxy)Benzene Sulfonamides; L. H. Sternbach et al. in J. Org. Chem. 26, 448 (1961); and L. H. Sternbach et al. in J. Org. Chem. 27, 3781 (1962).

The Z-aminobenzonitrile reactants employed in the new and novel second above-described process may be prepared by the procedures described by: S. Gabriel in Ber. 36, 804 (1903); I. Pinnow and C. Samann in Ber. 29, 624 (1896); W. Borsche, H. Weussman and A.

9 Fritzsche in Ber. 57, 1151 (1924); and L. H. Sternbach et al. in J. Org. Chem. 27, 3781 (1962).

The anthranilic acid reactants employed in the third above-described process may be prepared by the procedures described in the text Chemistry of Carbon Compounds vol. 3A, pp. 576-8, Editor E. H. Rodd, Elsevien, New York (1954).

The following examples are given by way of illustration.

EXAMPLE '1 Hydrogen chloride (gas) is bubbled into a hot melt of 2-amino-5-chlorobenzophenone (11.58 g., 0.050 In.) and 1-methyl-4-piperidone (5.66 g., 0.050 m.) for several minutes. An exothermic reaction takes place, with the concurrent evolution of water, and the melt solidifies. The melt is heated at ZOO-210 C. for one-half hour, cooled, and triturated with 2-propanol to yielding a colorless solid which is recrystallized from methanol-water. In this manner, colorless prisms of 8-chloro-l,2,3,4-tetrahydro-2-methyl phenylbenzo[b] [1,6] naphthyridine hydrochloride are obtained (1.4 g., 9%), M.P. 28590 C. 6-0Norris A. Bucksell--1l899-Day Patents-May 3 Analysis.Calcd. for c H ClgN (percent): C, 66.08; H, 5.26; N, 8.12. Found (percent): C, 65.76; H, 5.10; N, 8.12.

EXAMPLE II A mixture of 2-amino-5-chlorobenzophenone (11.53 g., 0.050 m.), polyphosphoric acid (330 g.), and l-methyl-4- piperidone (5.66 g., 0.050 m.) is heated gradually to 205 C. with stirring, and maintained at that temperature for one-half hour. The partially cooled reaction mixture (100-110" C.) is poured with stirring into a mixture of ice and water (500 g.). The resulting solution is filtered to remove a small amount of insoluble solid, then basified with 50% sodium hydroxide (120 cc.). The product separates as a crystalline solid, which is collected, washed thoroughly with water, and dried, M.P. 148 C. (uncorr.). Recrystallization from hexane yields pale yellow prisms of 8-chloro 1,2,3,4 tetrahydro-Z-methyl-lO-phenylbenzo [b][l,6] naphthyridine (9.0 g. 58.4%), M.P. 149.0- 149.5 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent); C, 73.90; H, 5.55; N, 9.07. Found (percent): C, 73.61; H, 5.28; N, 9.22.

Repeating of the above reaction at 145 C. for one hour produces a quantitative yield of the same product, M.P. 149.0149.5 C. (uncorr.).

EXAMPLE III A mixture of 2-amino-S-chlorobenzophenone (11.0 g.)

polyphosphoric acid (330 g.), and 1-benzyl-4-piperidone (5.8 g.) is heated gradually to about 200 -C. with stirring, and maintained at that temperature for threequarters of an hour. The partially cooled reaction mixture (100 C.) is poured with stirring into a mixture of ice and water (500 g). The resulting solution is filtered and then basified with 50% sodium hydroxide (120 cc.). The product separates as a yellow solid, which is collected, washed thoroughly with water and dried, M.P. 164-165 .5 C. (uncorr.). Recrystallization from 2-propanol afiords pale yellow, rhomboid crystals of 2-benzyl-8-cl1loro-1,2, 3,4-tetrahydro 10 phenylbenzo [b] [1,6] naphthyridine (19.35 g., 50.3%), M.P. 166.0166.5 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 78.00; H, 5.50; N, 7.28. Found (percent): C, 77.76; H, 5.27; N, 7.38.

In a similar manner, 2lbenzyl-7-bromo-1,2,3,4-tetrahydro 10 (p-tolyl)benzo [b] [1, 6] naphthyridine and Z-acetyl 1,2,3,4 tetrahydro 10 (p-methoxyphenyl-8 methylbenzo [b] [1,6] naphthyridine are obtained.

EXAMPLE IV Dry hydrogen chloride is passed into an ether solution of the above prepared 2-benzyl-8-chloro-1,2,3,4-tetrahydro-lO-phenylbenzo [b] [1,6] naphthyridine. Thereafter,

the corresponding hydrochloride salt is recrystallized from absolute ethanol to yield colorless crystals of 2-benzyl-8- chloro 1,2,3,4 tetrahydro 10 phenylbenzo [b] [1,6] naphthydridine hydrochloride, M.P. 271.5275 C. (uncorr.).

Analysis.--Calcd. for C H Cl N (percent): C, 71.25; H, 5.27; N, 6.65. Found (percent): C, 71.46; H, 5.42; N, 6.73. 5

EXAMPLE V 2-amino 5 chlorobenzophenone (23.17 g., 0.10 m.), polyphosphoric acid (600 g.), and 1 (2 phenethyl)-4- piperidone (20.33 g., 0.10 m.) are admixed, heated to C. with stirring, and maintained at that temperature for one hour. The reaction mixtureis cooled and, thereafter, is poured with stirring into a mixture of ice and water (1000 g.). The resulting solution is filtered to remove a small amount of insoluble solid, then basified with 50% sodium hydroxide (240 cc.). The resulting 8 chloro 1,2,3,4 te trahydro 2 (2-phenethyl)-10- phenylbenzo[b][l,6]naphthyridine separates as a solid which is dissolved in ether and treated with dry hydrogen chloride. In this manner, is obtained 8-chloro-1,2,3,4-tetrahydro 2 (2 phenethyl) l0 phenylbenzo[b][1,6]- naphthyridine hydrochloride, M.P. 268-269.5 C.

Analysis.-Calcd. for C H Cl N (percent): C, 71.71; H, 5.56; N, 6.44. Found (percent): C, 71.49; H, 5.49; N, 6.56.

Similarly, the following tetrahydrobenzonaphthyridine hydrochlorides are synthesized:

10- (p-bromophenyl -2-ethyl- 1 ,2,3,4- tetrahydro-7- nitrobenzo [b] 1,6]naphthyridine hydrochloride; IO-phenyl-1,2,3,4-tetrahydro-2-methylsulfoi1ylbenzo- [b] [1,6 ]naphthyridine hydrochloride; 8-ethyl-1,2,3,4-tetrahydro-l0-phenyl 2-propionylbenzo[b] [1,6] naphthyridine hydrochloride; and 7-ethoxy-2-ethyl-l,2,3,4-tetrahydro-10-phenylbenzo- [b] 1,6]naphthyridine hydrochloride.

EXAMPLE VI 1,2,3,4 tetrahydro 2 methyl 10 (2-pyridyl)benzo- [b] 1,6]naphthyridine.

Similarly, reacting 2-amino 5 iodophenyl 2 thienyl ketone and l-butyl 4 piperidone produces 2-butyl- 1,2,3,4 tetrahydro 8 iodo 10 (2-thienyl)benzo- [b][l,6] naphthyridine, while reacting Z-aminophenyl- 2 furyl ketone with 4-pi-peridone yields 10 -(2.-furyl)- l,2,3,4-tetrahydrobenzo [b] [1,6]naphthyridine.

EXAMPLE VII Repeating the procedure of Example VI to react the following o-aminocarbonyl compounds and 4-piperidones, the hereinafter listed tetrahydrobenzo naphthyridines are obtained.

Reactants Products 2-amiuo-5-chlorobenzophenone and 8-chlo1'o-2-(p-ehlorophenylsulfonyl) 1-(p-ehlorophenylsulfonyl)-4- 1,2,3,4-tetrahydro-lO-phenylbenzo piperidone. [b][l,6] naphthyridine. 2-amino-5-ehlorophenyl-2-thienyl S-chloro-l,2,3,4-tetrahydro-2- ketone and l-(dimethylcarbamoyD- dimethylearbamoyl-lO-(Z- 4-piperidone. thienyl) benzo[b][1,6]

naphthyridine. 2-amino-5-propylbenzophenone and 2-diethylcarbam0yl-l,2,3,4-tetra- 1-(diethylcarbamoyl)-4-piperidone. hydro-IO-phenyl-8-propylbenzo [b][l,6] naphthyridine.

1 1 EXAMPLE VIII Methyl iodide (2.29 g., 0.0162 m.) is added to a solution of 8-chloro-1,2,3,4-tetrahydro 2 methyl-- phenylbenzo [b][1,6] naphthyridine (5.0 g., 0.0162 In.) in absolute ether. The mixture is stored at room temperature in the dark overnight. The crystalline product which separates is recrystallized from 2-propanol to obtain colorless crystals of 8-chloro-1,2,3,4-tetrahydro-2,2-dimethyl 10 phenylbenzo [b][1,6] naphthyridinium iodide (1.8 g., 24.4%), M.P. 255256.5 C. (uncorr.).

Analysis.--Calcd. for C H ClN (percent): C, 53.28; H, 4.47; N, 6.42. Found (percent): C, 53.12; H, 4.76; N, 6.42.

Similarly, ethyl iodide is reacted with 2-ethyl-1,2,3,4- tetrahydro 7 methoxy 10 phenylbenzo [b][1,6] naphthyridine to produce 2,2-diethyl 1,2,3,4 tetrahydro 7 methoxy 10 phenylbenzo [b][1,6] naphthyridinium iodide.

EXAMPLE IX A solution of 2-benzyl 8 chloro 1,2,3,4 tetrahydro 10 phenylbenzo [b][1,6] naphthyridine (6.0 g., 0.0156 In.) in glacial acetic acid (100 ml.) containing platinum oxide (0.3 g.) is hydrogenated at room temperature, and an initial hydrogen pressure of 46.5 p.s.i. for a period of twenty-four hours. The excess acetic acid is distilled in vacuo, the residue dissolved in water, and then basified whereupon the crude product (5.87 g.) M.P. 160170 C. (uncorr.) separates. Recrystallization from cyclohexano-hexane affords colorless crystals of 2- benzyl 8 chloro 1,2,3,4,4a,5,10,10a octahydro-10- phenylbenzo [b][1,6] naphthyridine (2.19 g., 27.7%), M.P. 191.5193.5 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 77.21; H, 6.48; N, 7.20; CI, 9.11. Found (percent): C, 77.51; H, 6.32; N, 7.39; CI, 8.7.

EXAMPLE X Employing the procedure of Example IX upon the hereinafter listed above prepared tetrahydrobenzonaphthyridines, the following octahydrobenzonaphthyridines are produced.

S-chloro-l,2,3,4-tetrahydro-2 methyl-IO-phenylbenzo[b][1,6]- naphthyridine.

2-benzyl-7-bromo-1,2,3,4-tetrahydro-IO-(p-tolyl) benzo[b][1,6]- naphthyridine.

8-chl0ro-1,2,3,4-tetrahydro-2-(B- phenethyl)-10-phenyl-benzo[b]- [1,6]naphthyridine.

8-chlore-1,2,3,4-tetrahydro-2- methyl-10-(B-pyridyl) benz0[b]- [1,61naphthyridine.

8-chloro-1,2,3,4-tetrahydro-2- dimethylcarbamoyl-lO-(B- dine. S-chloro-I,2,3,4,5a,5,10,10a-0ctahydro-2-methyl-10-(BDiperidyl) benzo[b][l,6] naphthyridine. 8-chloro-1,2,3,4,4a,5,10,10a-octahydro-2-dimethylcarbamoyl-10- naphthyridme.

EXAMPLE XI A mixture of 2 amino-2,S-dichlorobenzophenone (26.61 g., 0.10 m.), polyphosphoric acid (500 g.) and 1- methyl-4-piperidone (11.32 g., 0.10 m.) is heated to reflux with stirring, and maintained at that temperature for two hours. The cooled reaction mixture is poured with stirring into a mixture of ice and Water (1000 g.). The resulting solution is filtered and then basified with 50% sodium hydroxide (120 cc.). The product separates as a yellow crystalline solid, which is collected, washed thoroughly with water, and dried. In this manner, is obtained 8-chloro-10-(o-chlorophenyl) 1,2,3,4 tetrahydro 2- methylbenzo [b][1,6] naphthyridine (31.2 g., 91.0%), M.P. 156.6-157.5 C.

By the procedure of Example IV, the above prepared base is converted to 8-chloro-10-(o-chlorophenyl)1,2,3,4- tetrahydro-Z-methylbenzo [b][1,6] naphthyridine hydrochloride, M.P. 275279 C. (uncorr.).

12 Analysis.Calcd. for C H Cl N (percent): C, 60.11; H, 4.51; Cl, 28.01; N, 7.37. Found (percent): C, 60.40; H, 4.41; Cl, 27.2; N, 7.65.

EXAMPLE XII The procedure of Example XI is repeated to prepare the following tetrahydrobenzo [b] [1,6] naphthyridine hydrochlorides from the corresponding starting compounds:

10- (p-ethylphenyl)-2-ethylsulfonyl-1,2, 3 ,4-tetrahydrobenzo [b] [1,6] naphthyridine hydrochloride;

7-butoxy-1,2,3,4-tetrahydro-10-(p-methoxyphenyl)- 2-phenylsulfonylbenzo b] 1,6] naphthyridine hydrochloride;

1,2,3 ,4-tetrahydro-2-methoxyethyl- IO-phenylbenzo- [b] [1,6]naphthyridine hydrochloride;

1,2,3,4-tetrahydro-2-dimethylaminoethyl-10-phenylbenzo- [b] [1,6]naphthyridine hydrochloride; and

7-bromo-10-(p-ethoxyphenyl)-1,2,3,4-tetrahydrobenzo- [b] 1,6] naphthyridine hydrochloride EXAMPLE XIII A mixture of Z-aminobenzophenone (5.0 g., 0.0368 m.), polyphosphoric acid (350 g.) and 1-benzyl-4-piperidone (5.66 g., 0.050 m.) is heated to reflux overnight. The cooled reaction mixture is poured with stirring into a mixture of ice water. The resulting solution is filtered to remove a small amount of insoluble solid, then basified with 50% potassium hydroxide cc.). The product separates as a crystalline solid, which is collected, washed thoroughly with Water, and dried. In this manner, is obtained 2 benzyl 1,2,3,4 tetrahydro-10-phenylbenzo [b] [1,6]naphthyridine which is dissolved in ether and treated with dry hydrogen chloride to yield the corresponding dihydrochloride salt.

In a similar manner, 2-benzyl-1,2,3,4-tetrahydro-10 phenylbenzo[b][1,6]naphthyridine hydrobromide and 1,2,3,4-tetrahydro 2 methoxypropyl-IO-phenylbenzo [b] [1,6]naphthyridine hydrochloride are synthesized.

EXAMPLE XIV Z-amino-5-chlorobenzophenone (11.58 g., 0.050 m.), polyphosphoric acid (330 g.), and 2,2,6,6-tetramethyl4- piperidone (7.76 g., 0.050 m.) are admixed, heated gradually to C. with stirring, and maintained at that temperature for three hours. The reaction mixture is cooled to 100 C. and is poured with stirring into a mixture of ice and water (600 g.). The resulting solution is filtered to remove a small amount of insoluble solid, then basified with 25% potassium hydroxide (240 cc.). The crude product separates as a crystalline solid which is filtered, Washed and dried, (9.1 g.). Upon recrystallization from hexane, there is obtained colorless prisms of 8-chloro-1,2,3,4-tetrahydro-1,1,3,3-tetramethyl-10-phenylbenzo [b][1,6] naphthyridine (4.30 g., 24.5%) M.P. 176178 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 75.32; 22.72; N, 8.37. Found (percent): C, 75.38; H, 5.56; N,

The above prepared base is converted by the procedure of Example IV to colorless prisms of the corresponding hydrochloride, M.P. 312 C.

Analysis.-Calcd. for C H Cl N (percent): C, 68.22; H, 6.25; Cl, 18.30; N, 7.23. Found (percent): C, 68.00; H, 6.44; CI, 18.00; N, 6.95.

EXAMPLE XV 2-amino-2,S-dichlorobenzophenone (13.31 g., 0.050 m.) is reacted with 2,2,6,6-tetramethyl-4-piperidone (7.76 g., 0.050 m.) by the procedure described in Example XIV to produce colorless prisms of 8-chloro-10 (o-chlorophenyl)-1,2,3,4-tetrahydro-1,1,3,3 tetramethylbenzo [11] [1,6] naphthyridine, M.P. 194-195 C. (uncorr.).

Analysis.Calcd. for C H Cl N (percent): C, 68.57; H, 5.76; Cl, 18.40; N, 7.27. Found (percent): C, 68.63; N, 5.81; Cl, 18.1; N, 7.07.

The above prepared base is converted to the hydrochloride in a manner similar to that of Example IV and colorless crystals thereof are obtained from 95% ethanol, M.P. 310 C. (uncorr.).

Analysis.-Calcd. for C H Cl -N (percent): C, 62.64; H, 5.49; CI, 25.22; N, 6.64. Found (percent: C, 62.60; H, 5.56; Cl, 25.2; N, 6.75.

The procedure of Example XIV is again repeated reacting a 2-amino-5-substituted benzophenone with a 2,2,6,6-tetramethyl-4-piperidone to synthesize the following compounds:

8-bromo-1,2,3,4-tetrahydro-1, 1,3 ,3-tetramethyl-10- phenyl-Z-propoxyethylbenzo [b] 1,6] naphthyridine;

2-(p-bromophenyl) -1,-2,3 ,4-tetrahydro-10-(p-iodophenyl)- 1,1,3 ,3 -tetramethylbenzo [b] [1,6] naphthyridine;

8-chlorol ,2,3 ,4-tetrahydro-1,1,3 ,3-pentamethyl- 10- phenylbenzo [b] [1,61naphthyridine; and

8-chlorol ,2,3 ,4-tetrahydr-1,1,3 ,3 -tetramethyl--(pmethyphenyl benzo [b] 1 ,6] naphthyridine.

EXAMPLE XVII 2-amino-5-chlorobenzophenone (16.62 g., 0.0718 m.), polyphosphoric acid (500 g.) and tropinone (10.0 g., 0.0718 m.) are mixed, heated to 150 C. with stirring, and maintained at that temperature for one-half hour. Thereafter, upon cooling the reaction mixture is poured into a mixture of ice and water (500 g.) with stirring. The solution is filtered, basified with 10 N sodium hydroxide, and the resulting solid is separated by filtration (21.3 g., 88.8%), M.P. 175177 C. (uncorr.). Upon recrystallization from a benzone-hexane mixture, there is obtained colorless prisms of 8-chloro-1,2,3,4-tetrahydro-2-methyl- 10-phenyl-1,3-ethanobenzo [b] [1,6]naphthyridine (13.6 g., 56.7%), M.P. l90-191 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 75.32; H, 5.72; N, 8.37. Found (percent): C, 75.38; H, 5.56; N, 8.44.

The corresponding hydrochloride is prepared as colorless crystals from ethanol, M.P. 310 C.

Analysis.-Calcd. for C H Cl N (percent): C, 67.93; H, 5.43; C], 19.10; N, 7.54. Found (percent): C, 67.65; H, 5.33; Cl, 18.9; N, 7.55.

EXAMPLE XVIII A mixture of 0.0346 m. of 2-amino-3-chlorobenzophenone, 0.0346 m. of 1-benzoyl-4-piperidone hydrochloride and 35 ml. of trifluoroacetic acid is refluxed for three hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is then extracted with a 20 percent aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product. Recrystallization of the free base from hexane affords a white solid which is 2-benzoyl-8-chloro-1,2,3,4-tetrahydro-10-phenylbenzo [b] [1,6]naphthyridine, M.P. 1956 C.

Analysis.Calcd. for C H Cl'N O (percent): C, 75.27; H, 4.80; N, 7.03; Cl, 8.89. Found (percent): C, 75.00; H, 4.48; N, 7.03; CI, 8.7.

EXAMPLE XIX 14 Analysis.-Calcd. for 0 1 1 0181 0, (percent): C, 68.76; H, 5.22; N, 7.63; Cl, 9.66. Found (percent): C, 68.93; H, 4.96; N, 7.77; Cl, 9.7.

Similarly, 2 butoxycarbonyl 1,2,3,4 tetrahydro 10 phenylbenzo[ b] [1,6]naphthyridine is produced.

EXAMPLE XX A solution of 8-chloro-2-ethoxycarbonyl-1,2,3,4-tetrahydro 10 phenylbenzo[b][1,6]naphthyridine (0.7 g. 0.0019 m.), as prepared above, in potassium hydroxide (5 g.), n-propyl alcohol (20 ml.) and water (0.5 ml.) is refluxed for three hours. The solution is evaporated and the residue dissolved in benzene followed by extraction with water. Evaporation of the benzene solution gives the product (0.5 g., 92%, M.P. 3 C.). Recrystallization from cyclohexane-hexane affords yellow crystals of 8- chloro 1,2,3,4 tetrahydro 10 phenylbenzo[b][l,6] na-phthyridine, M.P. 1379 C.

Analysis.Calcd. for C H ClN (percent): C, 73.34; H, 5.13; N, 9.51; Cl, 12.03. Found (percent): C, 72.75; H, 5.09; N, 9.44; Cl, 11.7.

Similar treatment of the above prepared 2-butoxycarbonyl 1,2,3,4 tetrahydro 10 phenylbenzo[b][l,6] naphthyridine affords 1,2,3,4-tetrahydro-lO-phenylbenzo [b] [1,6]naphthyridine.

EXAMPLE XXI To a solution of 8-chloro-1,2,3,4-tetrahydro-10-phenylbenzo[b] [1,6]naphthyridine (2.0 g., 0.00683 m.) in tetrahydrofuran (20 ml.) and 10% aqueous sodium hydroxide (10 ml.) at 0 C. is slowly added chloroacetyl chloride (0.6 ml., 0.08 In.) and stirred for forty-five minutes. Water (100 ml.) is added and the product collected (2.3 g.) M.P. 15 0-2" C. Recrystallization from benzene-hexane aflords 8 chloro 2 chloroacetyl 1,2,3,4 tetrahydro 10-phenylbenzo[b] [1,6]naphthyridine as yellow crystals, M.P. 1589 C.

Analysis.Calcd. for C H Cl N O (percent): C, 64.70; H, 4.35; N, 7.55; Cl, 19.5. Found (percent): C, 64.98; H, 4.23; N, 7.70; Cl, 19.0.

Repeating the aforesaid procedure to react an appropriate tetrahydrobenzonaphthyridine with a haloalkanoyl chloride, the following compounds are prepared: 10-phenyl 2 (3-bromopropionyl) l,2,3,4-tetrahydrobenzo [b] [1,6 naphthyridine; 7-methoxy Z-iodoacetyl 1,2,3,4-tetrahydro 10-phenylbenzo [b] [1,6] naphthyridine; and 2-fluoroacetyl-1,2,3,4 tetrahydro-10 phenylbenzo[b] 1,6] naphthyridine EXAMPLE XXII A solution of 8-chloro-1,2,3,4-tetrahydro 10 phenylbenzo[b][1,6]naphthyridine (5.0 g., 0.017 m.), glycidol (1.26 g., 0.017 m.) and xylene (40 ml.) is refluxed for fifteen hours. Evaporation of the solution gives an oil which afford a solid upon extraction with cyclohexane. Recrystallization from ethyl acetate affords 8-chloro-2- (2,3-dihydroxypropyl)-1,2,3,4 tetrahydro 10 phenylbenzo[b][1,6]naphthyridine, light yellow solid, M.P. 154-5 C.

Analysis.-Calcd. for C H ClN O (percent): C, 68.37; H, 5.74; N, 7.58; Cl, 9.62. Found (percent): C, 68.10; H, 5.82; N, 7.81; Cl, 9.4.

In a similar manner, 8-bromo-2-(2,3-dihydroxybutyl)- 1,2,3,4-tetrahydro 10 phenylbenzo[b][1,6]naphthyridine is synthesized.

EXAMPLE XXIII A mixture of 8-chloro-1,2,3,4-tetrahydro 10 phenylbenzo[b] [1,6]naphthyridine (8.5 g., 0.029 m.) and 1- guanyl-3,S-dimethylpyrazole nitrate (2.9 g., 0.0144 in.) is ground together and stirred under nitrogen at 160-5 C. for two hours. Upon cooling the gum is heated with ethyl acetate (30 ml.) and the product filtered after cooling (4.7 g., 0.0117 m., 82%). Recrystallization from 15 ethanol-water affords white crystals of 2 amidino-S- chloro 1,2,3,4 tetrahydro 10 phenylbenzo[b] [1,6] naphthyridine nitrate, M.P. 270-1 C. decomp.

Analysis.-Calcd. for C H ClN-HNO (percent): C, 57.07; H, 4.34; N, 17.52; Cl, 8.87. Found (percent): C, 57.14; H, 4.50; N, 17.34; Cl, 8.8.

EXAMPLE XXIV A solution of 8-chloro-2-chloroacetyl-1,2,3,4-tetrahydro 10 phenylbenzo[b][1,6]naphthyridine (6.0 g., 0.0161m.), diethylamine (3.4 ml., 0.0322 m.), anhydrous potassium carbonate (4.45 g.) and dimethyl formarnide (50 ml.) is heated at 55 C. for three hours. Filtration and evaporation of the solvent gives a gum. This is dissolved in methylene chloride, extracted with water and evaporated giving an oil. The oil is dissolved in a 2% hydrochloric acid solution and filtered. The filtrate is made alkaline, extracted with methylene chloride and evaporated giving a gum. The crude base is added to a hot solution of p-toluene sulphonic acid in tetrahydrofuran. A solid is obtained and recrystallization from tetrahydrofuranethanol affords white crystals of 8-chloro-2- (2-diethylaminoacetyl)-1,2,3,4-tetrahydro 10 phenylbenzo[b][1,6]naphthyridine di-p-toluene sulfonate, M.P. 2256 C. decomp.

Analysis. Calcd. for CZ4H2GCIN3O'ZC7H8O3SZ C, 60.67; H, 5.63; N, 5.59; Cl, 4.7. Found (percent): C, 60.70; H, 5.35; N, 5.74; Cl, 4.8.

In a similar manner, the following compounds are prepared:

1,2,3,4-tetrahydro-2-(3-dimethylaminopropionyl) 10- (p toly1)benzo[b][l,6]naphthyridine dihydrochloride; and

1,2,3,4-tetrahydro-7-methyl 10 phenyl 2 (4-dipropylaminobutyryl)benzo[b][1,6]naphthyridine di ptoluene sulfonate.

EXAMPLE XXV To a solution of 8-chloro-1,2,3,4-tetrahydro-10-phenylbenzo[b] [1,6]naphthyridine (6.0 g., 0.0204 m.), triethylamine (3.34 ml., 0.024 m.) and tetrahydrofuran (100 ml.) at C. is slowly added dichloroacetyl chloride (2.02 ml., 0.021 m.) and the mixture is stirred for two hours. Evaporation of the tetrahydrofuran gives a solid which is slurried with chloroform and water. The water is separated and the product recrystallized from benzene affording white crystals of 8-chloro-2-dichloroacetyl-1,2,3,4- tetrahydro 10-phenylbenzo[b][1,6]naphthyridine, M.P. 215-6 C.

Analysis. Calcd. for C H Cl N O (percent): C, 59.20; H, 3.72; N, 6.91; CI, 26.2. Found (percent): C, 59.70; H, 3.92; N, 6.53; Cl, 25.8.

EXAMPLE XXVI A mixture of 0.0346 111. of 2-amino-3-chlorobenzophenone, 0.0346 m. of 1-(3-dimethylaminopropyl-4-piperidone hydrochloride and 35 ml. of trifluoroacetic acid is refluxed for three hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product Which is converted to the maleate salt by interaction with maleic acid in acetone. Addition of ethyl ether precipitates the salt which is recrystallized from acetonitrile to yield 8-chloro- 2 (3-dimethylaminopropyl) 1,2,3,4-tetrahydro 10- phenylbenzo[b][1,6]naphthyridine dimaleate, M.P. 173- 4 C. decomp.

Analysis.-Calcd. for C H ClN -2C H O (percent): C, 60.83; H, 5.60; N, 6.86; Cl, 5.79. Found (percent): C, 60.67; H, 5.76; N, 6.80; CI, 5.8.

EXAMPLE XXVII A mixture of (0.0346 In.) 2-arnino-3,5-dichlorobenzophenone, (0.0345 m.) of 4-benzylpiperidone hydrochloride and 35 ml. of trifiuoroacetic acid is refluxed for three hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a 20% aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product as a brown gummy solid, which is collected, Washed thoroughly with Water, reacted with dry hydrogen chloride by the procedure of Example IV and recrystallized from n-propyl alcohol and water to afford yellow crystals of 2-benzyl 6,8-dichloro-1,2,31,4- tetrahydro-lO-phenylbenzo [b] [1,6]naphthyridine dihydrochloride, M.P. 272-3 C. decomp.

Analysis.-Calcd. for C H N Cl -HCl (percent): C, 65.87; H, 4.64; N, 6.14; Cl, 23.3. Found (percent): C, 65.71; H, 4.69; N, 5.98; Cl, 23.0.

EXAMPLE XXVIII Repeating the procedure of Example XXVII to react an appropriate Z-aminobenzophenone and a 4-piperidone, the hereinafter listed tetrahydronaphthyridines are obtained:

8-ethyl-2-(2,3-dihydroxypropyl)-1,2,3,4-tetrahydro- IO-phenylbenzo [b] [1,6] naphthyridine; 8-bromo-1,2,3,4-tetrahydro-Z-methoxycarbonyl-10- phenylbenzo [b] [1,6] naphthyridine; 10-phenyl-Z-chloroacetyl-1-2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine; 2-amindo-1,2, 3 ,4-tetrahydro-101-phenyl-7-propylbenzo [b] [1,6] naphthyridine; 8-bromo-2-(Z-diethylaminoacetyD-1,2,3,4-tetrahydro- 10-phenylbenzo [b] 1,6] naphthyridine; 2- (2-,2-dichloroacetyl) -1,2,3 ,4-tetrahydro-10- (p-tolyl benzo [b] 1,6] naphthyridine; 10- (p-bromophenyl -1,2,3,4-tetrahydro-2,7-dimethyl- 8-methylsulfonylbenzo [b] 1,6] naphthyridine; 2-ethyl- 1 ,2,3,4-tetrahydro- 1 0-pheny1-8-sulfamoylbenzo [b] 1,6] naphthyridine; 10-phenyl-7-chloro-1,2,3 ,4-tetrahydro-8-su1famoylbenzo [b] [1,6] naphthyridine; 7-carbamoyl-8-trifiuoromethyl-1,2,3,4-tetrahydro- 10-phenylbenzo [b] 1,6 naphthyridine; 6,9-diethoxy-Z-ethoxycarbonyl-1,2,3,4-tetrahydro- 10- (p-propylphenyl) benzo [b] 1,6]naphthyridine; 8-trifiuromethyl-1,2,3,4-tetrahydro-2-methyl-10- phenylbenzo [b] 1,6] naphthyridine 7,8-diethyl-1,2,3 ,4-tetral1ydro-Z-methoxycarbonyl- IO-phenylbenzo [b] 1,6] naphthyridine; 7,9-dichloro-2-ethoxycarbonyl-1,2,3 ,4-tetrahydro- IO-p-tolyl benzo [b] 1,6] naphthyridine; 10-phenyl-1,2,3,4-tetrahydro-7,8-dimethoxy-2- methoxycarbonylbenzo [b] 1, 6] naphthyridine; 8-ethylthio-1,2,3 ,4-tetrahydro-2- (2,3-dihydroxypropyl) -10-phenylbenzo [b] [1,6] naphthyridine; 2-ethoxycarbonyl-2,7-diethyl-1,2,3 ,4-tetrahydro- S-methylthio-10-phenylbenzo [b] 1,6] naphthyridine; and 1,2,3,4-tetrahydro-10-phenyl-2-propyl-8-propylsulfonylbenzo [b] [1,6] naphthyridine.

EXAMPLE XXIX Employing the procedure of Example 1X upon the tetrahydrobenzonaphthridines of Example XXVIII, the following octahydrobenzonaphthyridines are prepared:

8-ethyl-2-(2,3-dihydroxypropyl)-1,2,3,4,4a(5,10,10aoctahydro- 1 O-phenylbenzo [b] 1,6] nahythyridine; 8-bromo-2-methoxycarbonyl-1,2,3 ,4,4a,5,10,10a-

octahydro- 10-phenylbenzo [b] [1,6 naphthyridine; 10-phenyl-2-chloroacetyl- 1,2,3 ,4,4a,5,10,10aoctahydrobenzo [b] [1,6] naphthyridine; 2-amidino-1,2,3,4,4a,5,10,10a-octahydrobenzo-10- phenyl-7-propylbenzo [b] [1,6 naphthyridine; 8-bromo-2- (2-diethylaminoacetyl) -1,2,3,4,4a,5-10-10aoctahydro- 1 O-phenylbenzo [b] 1,6 naphthyridine 2- (2,2-dichloroacetyl) -1,2,3,4,4a,5,10,10a-octahydro- 10- (p-tolyl)benzo [b] 1,6] naphthyridine;

10-(p-bromophenyl) -1,2,3,4,4a,5,10,10a-octahydro-2,7-

dimethyl- 8-methylsulfonylb enzo [b] 1,6] naphthyridine;

2-ethy1-1,2,3,4,4a,5,10,10a-actahydro-10-phenyl- 8-sulfamoylbenzo [b] 1,6] naphthyridine;

10-phenyl-7-chloro-l,2,3 ,4,4a,5,10,10a-octahydro- 8-sulfamoylbenzo [b] 1,6] naphthyridine;

7-carb amoyl-S-trifluoromethyl- 1,2, 3 ,4,4a,5,10,10a-

octahydro-l O-phenylb enzo [b] 1,6]naphthyridine;

6,9-diethoxy-2-ethoxycarbonyl-1,2,3,4,4a,5,10,10a-

octahydro-10- (p-propylphenyl benzo [b] 1,6] naphthyridine;

S-trifluoromethyl-1-,2,3,4,4a,5,10,10a-octahydro- Z-methyl-l O-phenylbenzo [b] 1,6] naphthyridine;

7,8-diethyl-1,2,3,4,4a,5,10,10a-octahydro-2-methoxycarbonyl- 1 O-phenylb enzo [b] 1,6]naphthyridine;

7,9-dichloro-2-ethoxycarbonyl-l,2,3,4,4a,5,10,10a-

octahydro-lO-(p-to1yl)benzo [b] [1,6] naphthyridine;

IO-phenyl-l,2,3,4,4a,5,10,10a-octahydro-7,8-dimethoxy 2-methoxycarbonylbenzo [b] 1,6] naphthyridine;

8-ethylthio-1,2,3,4,4a,5,10,10a-octahydro-2- (2,3-dihydroxypropyl) -10-phenylbenzo [b] 1,6] naphthyridine;

Z-ethoxycarbonyl-2,7-diethyl-1,2,3 ,4,4a,5, 10, 10aoctahydro-S-methylithio-lo-phenylbenzo [b] [1,6] naphthyridine; and

1,2,3,4,4a,5,10,10a-octahydro-l-phenyl-2-propyl- 8-propylsulfonylbenzo [b] 1,6] naphthyridine.

EXAMPLE XXX To a solution of 252.0 g. (4.5 m.) of potassium hydroxide (assay 85%) in 500 ml. of methanol there are added with stirring and cooling in an ice bath 41.2 g. (0.28 m.) of p-methoxyphenylacetonitrile and a solution of 50.0 g. (0.26 m.) of 3,4-dichloronitrobenzene in 400 ml. of methanol. The mixture is stirred for four hours at 0-5 C. and then 3000 ml. of water is added with stirring. The precipitate is isolated by filtration, dissolved in methylene chloride, washed with water, dried and evaporated. The residue is recrystallized from benzene-hexane giving 23 g. (30%) of 5,6-dich1oro 3 (p-methoxyphenyl)-2,l-benzisoxazole. A second recrystallization of the product from npropanol gives the pure crystalline solid, M.P. 1568 C. (incorr.).

Analysis.Ca1cd. for C ,,l-I Cl NO (percent): C, 57.17; H, 3.11; N, 4.76; Cl, 24.11. Found (percent): C, 57.37; H, 3.16; N, 5.04; CI, 24.8.

A mixture of 2.0 g. (0.0682 m.) of the above prepared 5,6-dichloro-3-(p-methoxyphenyl)-2,1 benzisoxazole, 0.1 g. of 10% palladium on charcoal and 75 ml. of ethyl acetate in a sealed vessel is treated with hydrogen gas at l-2 atm. and heated to 55 C. for five hours. The solution is filtered and evaporated giving 1.5 g. (74%) of Z-amino- 4,5-dichloro-4-methoxybenzophenone which is recrystallized from absolute ethanol to afford the pure crystalline solid, M.P. 169170 C. (uncorr.).

Analysis.Calcd. for C H Cl NO (percent): C, 56.76; H, 3.75; N, 4.73; Cl, 23.94. Found (percent): C, 56.72; H, 3.69; N, 4.67; Cl, 23.8.

A mixture of 5.0 g. (0.168 m.) of 2-amino-4,5-dichloro- 4'-methoxybenzophenone 3.5 g. (0.185 m.) of l-benzyl- 4-piperidone hydrochloride and 35 ml. of trifiuoroacetic acid is refluxed for three hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a 20% aqueous potassium hydroxide solution. The methylene chloride solu- I tion is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product which is recrystallized from ethylacetate to afford 4.5 g. (60%) of product. A second recrystallization from tetrahydrofuran gives 2-benzyl-7,8-dichloro-1,2,3,4-tetrahydro-10- (p-methoxyphenyl)benzo[b] [1,6]naphthyridine as crystalline solid, M.P. 1956 C. (uncorr.).

Analysis.--Calcd. for C H Cl N O (percent): C, 69.49; H, 4.71; N, 6.24. Found (percent): C, 69.50; H, 4.89; N, 6.30.

Employing the procedure of Example ]X, the above product is converted to 2-benzyl-7,8-dichloro-1,2,3,4,4a,5, 10,10a-octahydro-10 (p methoxyphenyl)benzo [b] [1,6] naphthylridine.

EXAMPLE XXXI Z-amino-S-chloro 3' sulfamylbenzophenone (3.0 g., 0.00965 In.) prepared by the procedure described in copending United States Patent No. 3,516,992 of June 9, 1975 entitled 3-(2-Amino-5-Halo-S-Alkyl-and-S-Alkoxy) Benzene Sulfonamides, filed on Jan. 18, 1967 by Stanley C. Bell, is reacted with l-benzyl-4-piperidone (1.82 g., 0.00965 m.) in the manner which is described in Example )OCX. Several recrystallizations of the free base from benzene affords m-(2-benzyl-8-chloro-l,2,3,4-tetrahydro- 10-benzo [b] [1,6]naphthyridinyl)benzenesulfonamide as a crystalline solid, M.P. 189193 C. (uncorr.).

Analysis.-Calcd. for C H ClN O S (percent): C, 64.72; H, 4.78; N, 9.06; Cl, 7.64. Found (percent): C, 64.67; H, 5.00; N, 9.15; Cl, 7.7.

When the above product is hydrogenated by the process of Example IX, there is obtained m-(2-benzyl-8-chloro- 1,2,3,4,4a,5,10,10a octahydro 10 benzo[b] [1,6]naphthyridinyl)benzenesulfonamide.

EXAMPLE XXXII A mixture of 7.0 g. (0.03 m.) of 2-amino-3-chlorobenzophenone, 5.5 g. (0.03 m.) of 1-benzyl-4-piperidone hydrochloride and 35 m1. of trifluoroacetic acid is refluxed for three hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a 20% aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product as a brown oil. The hydrochloride salt is prepared in a methylene chloride solvent. Evaporation of the solvent and recrystallization of the residue from acetonitrile gives 2-benzyl-6-chloro- 1,2,3,4 tetrahydro 10 phenylbenzo [b] [1,6] naphthyridine hydrochloride as a crystalline solid (7.0 g., 59%) M.P. 241-2 C. (uncorr.).

Analysis.--Calcd. for C H ClN -HCl (percent): C, 71.25; H, 5,27; N, 6.65; Cl, 16.8. Found (percent): C, 70.92; H, 5.15; N, 6.85; Cl, 16.9.

In the same manner, reacting the following Z-aminobenzophenones and 4-piperidones the hereinafter products are obtained:

2-amino-5,4'-dichlorobenzophenone (3.8 g., 0.014 m.) is reacted with 1-benzyl-4-piperidone (2.69 g., 0.014 m.) The free base is extracted with hexane giving 2.8 g. (47%) or product as a crystalline solid which is recrystallized twice from cyclohexane to afford 2-benzy1-8- chloro- 10-(p chlorophenyl) 1,2,3,4 tetrahydrobenzo [b] [1,6] naphthyridine, M.P. 6 C. (uncorr.).

Analysis.Ca1cd. for C H Cl N (percent): C, 71.61; H, 4.81; N, 6.68; CI. 16.91. Found (percent): C, 71.84; H, 5.02; N, 6.56; Cl, 16.6.

2-amino-5-chloro 4' methoxybenzophenone (5 .0 g., 0.019 m.) is reacted with 1-benzyl-4-piperidone (3.6 g., 0.019 m.) Recrystallization of the free base from cyclohexane aflords 4.0 g. (51%) of crude product which is recrystallized twice from benzene-hexane to yield 2-benzyl- 8 chloro 1,2,3,4 tetrahydro 10 (p-methoxyphenyl) benzo[b][1,6]naphthyridine as a crystalline solid, M.P. 176-7 C. (uncorr.).

Analysis.-Calcd. for C H ClN O (percent): C, 75.26; H, 5.59; N, 6.92; Cl, 8.54. Found (percent): C, 755.30; H, 5.48; N, 6.58; Cl, 8.45).

2-amino-4'-methylbenzophenone (6.0 g., 0.028 m.) is reacted with 2,2,6,6-tetramethyl-4-piperidone hydrochloride (5.5 g., 0.028 m.). Recrystallization of the free base from hexane gives 1,2,3,4-tetrahydro-1,1,3,3-tetramethyl- 19 10-(p-tolyl)benzo[b][1,6]naphthyridine as a crystalline solid, M.P. 1913 C. (uncorr.).

Analysis.-Calcd. for C H N (percent): C, 83.58; H, 7.93; N, 8.49. Found: (percent) C, 83.23; H, 7.73; N, 8.34.

Employing the procedure of Example IX, the above products are converted to the following:

2-benzyl-6-chloro-1,2,3 ,4,4a,5,10,10a-octahydrophenylbenzo [b] [1,6 naphthyridine;

2-benzyl-8-chloro- 10- (p-chlorophenyl) 1 ,2,3,4,4a,5, 10,10a-octahydrobenzo [b] [1,6 naphthyridine;

2-benzyl-8-chloro-1,2,3 ,4,4a,5,10,10a-octahydro-10- (p-methoxyphenyl) benzo [b] [1,6] naphthyridine; and

1,2,3,4,4a,5,10,10a-octahydro-1,1,3,3-tetramethyl-10- (p-tolyl benzo [b] [1,6] naphthyridine EXAMPLE XXXIII A mixture of 8.0 g. (0.0346 m.) of 2-amino-3-chlorobenzophenone, 6.63 g. (0.0346 In.) of 2,2,6,6-tetramethyl- 4-piperidone hydrochloride and 35 ml. of trifluoroacetic acid is refluxed for three hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a 20% aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product. Recrystallization of the free base from hexane affords 6-chloro-1,2,3,4- tetrahydro 1,1,3,3 tetramethyl 10 phenylbenzo[b] [1,6]naphthyridine as a crystalline solid, (46%), M.P. 1678 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 75.30; H, 6.61; N, 7.98. Found (percent): C, 75.14; H, 6.66; N, 7.97.

Similarly, 2 amino 4,5,4'-trimethoxybenzophenone (5.0 g., 0.0174 in.) is reacted with 2,2,6,6-tetramethylpiperidone hydrochloride (3.34 g., 0.0174 m.). The free base is dissolved in absolute ethanol, filtered and the solvent evaporated. Recrystallization of the residue from cyclohexane affords 7,8 dimethoxy 1,2,3,4 tetrahydro- 1,1,3,3 tetramethyl 10 (p-methoxyphenyl)benz[b] [1,6]naphthyridine as a crystalline solid, 2.7 g. (37%), M.P. 179-182" C. (uncorr.).

Analysis.Ca1cd. for C25H30N203: C, H, N, 6.89. Found (percent): C, 73.73; H, 7.58; N, 6.63.

When the above products are hydrogenated by the process of Example IX, the following compounds are obtained: 6 chloro 1,2,3,4,4a,5,10,10a octahydro-1,1,3,3- tetramethyl phenylbenzo [b] [1,6]naphthyridine; and 7, 8 dimethoxy 1,2,3,4,4a,5,10,10a octahydro-1,l,3,3- tetramethyl 10 (p-methoxyphenyl)benzo [b] [1,6] naphthyridine.

EXAMPLE XXXIV A Grignard reagent prepared from 66.8 (0.41 m.) of 2-bromothiophene and 11.4 g. (0.45 In.) of magnesium in 200 ml. of ether is slowly added over a period of onehalf hour to a solution of 80.0 g. (0.41 m.) of 2-methy1- 7-chloro-4H-3,1-benzoxazin-4-one, prepared as described in Ind. J. Pharm. by Somasekhara et a1. 27, 1213 (1965), in 575 ml. of benzene keeping the temperature at 15-20 C. during the addition. The reaction mixture is then stirred for forty-five minutes at 5060 C. After cooling to C., the complex is decomposed by the slow addition of 350 ml. of 2 N hydrochloric acid. The organic layer is separated, Washed with dilute sodium hydroxide, water, dried over sodium sulfate and evaporated to dryness. The product is triturated with absolute ethanol and recrystallized from cyclohexane giving 2 acetamido-4- chlorophenyl 2 thienyl ketone as a crystalline solid, M.P. 100101 C. (uncorr.).

Analysis.Calcd. for C H ClNO S (percent): C, 55.80; H, 3.60; N, 5.00; CI, 12.67; S, 11.46. Found (percent): C, 55.76; H, 3.27; N, 5.00; Cl, 12.7; S, 11,1.

A solution of 59.4 g. (0.212 m.) of 2-acetamido-4- chlorophenyl-2-thienyl ketone in 1400 ml. of ethanol and 600 ml. 6 N hydrochloric acid is refluxed for four hours. The residue obtained, after evaporation of the solvent, is basified with sodium carbonate and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated leaving 39 g. of solid. Recrystallization of the product from cyclohexane gives 2 amino 4 chlorophenyl 2' thienyl ketone, M.P. 798l C., (uncorr.).

Analysis.Calcd. for C H ClNOS (percent): C, 55.55; H, 3.39; N, 5.89; Cl, 14.92; S, 13.49. Found (percent): C, 55.78; H, 3.19; N, 583; C1, 14.9; S, 13.4.

A mixture of Z-acetarnido-4-chlorophenyl-2-thienyl ketone (0.212 m.), 1-methyl-4-piperidone (0.021 m.) and 40 ml. of glacial acetic acid is refluxed for four hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a 20 percent aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product. Trituration of the free base with hexane gives 7 chloro 1,2,3,4 tetrahydro 2 methyl-10- (2 thienyl)benzo[b] [1,6]naphthyridine as a crystalline solid (4.8 g., 73%) M.P. 141-3 C. (uncorr.).

Analysis.-Calcd. for C H ClN S (percent): C, 64.86; H, 4.80; N, 8.89. Found (percent): C, 65.16; H, 4.91; N, 8.92.

When the above compound is hydrogenated by the procedure of Example IX, there is afforded 7 chloro- 1,2,3,4,4a,5,10,10a octahydro 2 methyl 10 (2- thienyl)benzo [b] [1,6] naphthyridine.

EXAMPLE XXXV Following the procedure described in Example XXXIV, 8.33 g. (0.41 m.) of 4-bromothioanisole, 11.4 g. (0.45 m.) of magnesium and 80.0 g. (0.41 m.) of 2-methyl-7-chloro- 4H 3,1 benzoxazin 4 one produce 5-chloro-2-(p methylthiobenzoyl)acetanilide. Recrystallization of the product from methanol affords a crystalline solid, wt. 31.0

g. (25%) M.P. 7 C. (uncorr.).

Analysis.Calcd. for C H CINO S (percent): C, 60.09; H, 4.41; N, 4.38. Found (percent): C, 59.94; H, 4.35; N, 4.47.

Following the procedure described in Example XXXIV, 26.2 g. (0.082 m.) of 5' chloro 2 (p-methylthiobenzoyl)acetanilide are hydrolyzed to give 24 g. M.P. 11923 C. of 2 amino 4 chloro-4-methylthiobenzophenone. Recrystallization of the product from cyclohexane affords a crystalline solid, M.P. 1224 C. (uncorn).

Analysis.Calcd. for C H ClNOS (percent): C, 60.52; H, 4.35; N, 5.04. Found (percent): C, 60.32; H, 4.29; N, 4.89.

A mixture of 5.0 g. (0.018 m.) of 2 amino 4-chloro- 4'-methylthiobenzophenone, 3.46 g. (0.018 m.) of 2,2,6,6- tetramethyl 4 piperidone hydrochloride and 35 ml. of trifluoroacetic acid is refluxed for three hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a 20% aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product. Recrystallization of the free base from hexane affords 7 chloro 1,2,3,4 tetrahydro 1,l,3,3 tetramethyl 10 (p methylthiophenyl)benzo[b] [1,6] naphthyridine as a crystalline solid 4.8 g. (67%), M.P. 1624 C. (uncorr.).

Analysis.--Calcd. for C H ClN S (percent): C, 69.58; H, 6.35; N, 7.06. Found (percent): C, 69.41; H, 6.05; N, 7.22.

In a similar manner, IO-(p-ethylthiophenyl)-1,2,3,4- tetrahydro l,l,3,3 tetramethylbenzo[b] [1,6]napl1thyri- 21 dine; and 10 (m butylthiophenyl)1,2,3,4 tetrahydro- 7 methylbenzo[b] [1,6]naphthyridine are produced.

EXAMPLE XXXVI Following the procedure described in Example XXXIV, 92.3 g. (0.41 In.) of 3-bromobenzotrifluoride, 11.4 g. (0.45 m.) of magnesium and 80.0 g. (0.41 m.) of 2- methyl 7 chloro 4H 3,1 benzoxazin-4-one produce 36 g. (26%) of 5' chloro 2'-(m-a,a,a-trifiuorotoluoyl) acetanilide, M.P. 8595 C., which is recrystallized from hexane, M.P. 86-8 C. (uncorr.).

Analysis.Calcd. for C H ClF NO (percent): C, 56.24; H, 3.24; N, 4.10. Found (percent): C, 56.16; H, 3.01; N, 3.91.

Following the procedure described in Example XXXIV, 21.5 g. (0.063 m.) of 5' chloro 2' (m-a,a,u-trifluorotoluoyl)acetanilide are hydrolyzed to give 18 g., M.P. 85-90 C., of 2 amino 4 chloro-3'-trifluoromethylbenzophenone. Recrystallization of the product from hexane affords a crystalline solid, M.P. 94-6" C. (uncorr.).

Analysis.Calcd. for C H C1F NO (percent): C, 56.10; H, 3.02; N, 4.67. Found (percent): C, 56.17; H, 2.93; N, 4.49.

2-amino-4-chloro-3-trifluoromethylbenzophenone (5.0 g., 0.0167 111.) and 2,2,6,6-tetramethyl-4-piperidone hydrochloride (3.2 g., 0.0167 111.) are allowed to react in a manner similar to Example XIV. The solution is poured into ice water and sodium hydroxide added to adjust the pH to 7. The insoluble product is filtered and recrystallized twice from a dimethylformamide-water mixture giving in (7 chloro 1,2,3,4-tetrahydro-1,1,3,3-tetramethylbenzo[b][1,6]naphthyridin-10-yl)benzoic acid as a crystalline solid, M.P. 310 C. (uncorr).

Analysis.Calcd. for C H ClN O (percent): C, 70.01; H, 5.87; N, 7.09. Found (percent) C, 69.73; H, 5.58; N, 7.20.

EXAMPLE XXXVII Following the procedure described in Example XXXIV, reacting 15.0 g. (0.095 m.) of bromobenzene, 2.47 g. (0.1 m.) of magnesium and 15.0 g. (0.077 m.) of 2-methyl-7- chloro-4H-3,1-benzoxazin-4- one produces a yellow oil. Trituration with a 20% cyclohexane-hexane solution gives 3.1 g. yield) of 5'-chloro-2'-benzoylacetanilide. Recrystallization of the product from cyclohexane affords a crystalline solid, M.P. 88-9 C. (uncorr.).

Analysis.--Calcd. for C H C1NO C, 65.82; H, 4.42; N, 5.11. Found (percent): C, 65.79; H, 4.45; N. 5.23.

The above compound is also prepared by an alternate procedure. To a same quantity of the Grignard reagent as prepared above is added in five minutes, 7.3 g. (0.04 m.) of anhydrous cadmium chloride and the solution is refluxed for minutes. The diethyl ether is distilled, replaced with 75 ml. of dry benzene and an additional 15 m1. of the solution is distilled. This slurry is added in thirty minutes to a solution of 15.0 g. (0.077 m.) of 2-methyl-7-chloro-4H-3,1-benzoxazin-4-one in 150 ml. of benzene, and then refluxed for forty-five minutes. After cooling to 20 C., the complex is decomposed by the slow addition of 100 m1. of 2 N hydrochloric acid. The resulting solid requires fine crushing before extraction with benzene and dilute hydrochloric acid. The organic layer is separated, washed with dilute aqueous sodium hydroxide, water, dried over anhydrous sodium sulfate and concentrade to dryness in vacuo. The residue is triturated with a 20% cyclohexane-hexane solution to give 8.3 g. (39% yield) of 5'-chloro-2'-benzoylacetanilide. Recrystallization of the product from cyclohexane afford a crystalline solid, M.P. 889 C. (uncorr.).

Following the procedure described in Example XXXIV, 5'-chloro-2'-benzoylacetanilide is hydrolyzed to give 2- amino-4-chlorobenzophenone, M.P. 84-5 C.

2-amino-4-chlorobenzophenone (5.0 g., 0.0215 In.) is allowed to react with 1-benzyl-4-piperidone (4.25 g., 0.0225 In.) in a manner similar to Example XXXV. Extraction of the free base with hexane gives 4.0 g. (48%) of the compound as a crystalline solid. Two recrystallizations from cyclohexane aifords 2-benzyl-7-chloro-1,2,3,4- tetrahydro 10 phenylbenzo [b] [1,6] naphthyridine, M.P. 142-3 C. (uncorr.).

AnalysiS.Calcd. for C H ClN C, 78.01; H, 5.50; N, 7.28. Found (percent) C, 77.60; H, 5.28; N, 7.05.

EXAMPLE XXXVIII A mixture of 3.5 g. (0.01 m.) of 8-chloro-1,2,3,4-tetrahydro 1,1,3,3 tetramethyl-10-phenylbenzo [b] [1,6]naphthyridine, 9.45 ml. (0.025 m.) of formic acid, 0.083 ml. (0.011 m.) of formalin and 75 ml. of isopropyl alcohol is refluxed for eight hour. The solution is acidified with 2.5 ml. of 12 N hydrochloric acid, evaporated, the solid residue dissolved in Water, the solution made alkaline and extracted with a 5 :-benzenezdiethy1 ether mixture. The organic solvent is evaporated and the residue recrystallized from hexane giving 8-chloro-1,2,3,4-tetrahydro-1,1,3,3- pentamethyl-10-phenylbenzo[b][1,6]naphthyridine as a crystalline solid, M.P. 1756 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 75.70; H, 6.90; N, 7.68. Found (percent): C, 75.81; H, 6.58; N, 7.63.

EXAMPLE XXXIX 2-aminobenzophenone (6.0 g., 0.0305 m.), l-(B-phenethyl)-4-piperidone (6.2 g., 0.0305 m.), 0.3 ml. of trifluoroacetic and 18 ml. of toluene are refluxed for twelve hours over a Dean Stark trap. The solution is evaporated and the residue extracted with hot hexane. Evaporation of the solvent followed by trituration with diethyl ether gives a solid. Recrystallization from diethyl ether affords 1,2,3, 4 tetrahydro 2-phenethyl-10-phenylbenzo [b] [1,6]naphthyridine as a crystalline solid, M.P. 1134 C. (uncorr.).

Analysis.Calcd. for C H N C, 85.67; H, 6.64; N, 7.69. Found (percent) C, 86.31; H, 6.56; N, 7.80.

EXAMPLE XL A mixture of 6.0 g. (0.0305 In.) of 2-aminobenzophenone, 5.77 g. (0.0305 m.) of l-benzyl-4-piperidone and 40 of glacial acetic acid is refluxed for four hours. The solution is evaporated under vacuum and the residue is dissolved in methylene chloride which is extracted with a 20% aqueous potassium hydroxide solution. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated giving the crude product. Trituration of the free base with hexane gives 9.5 g. 87%) of a solid. Recrystallization from cyclohexane gives 2-benzyl-1,2,3,4-tetrahydro-10-phenylbenzo[b] [1,6]naphthyridine as a crystalline solid, M.P. 1589 C. (uncorr.).

Analysis.Calcd. for C H N (percent): C, 85.69; 171956.33; N, 8.00. Found (percent): C, 85.92; H, 6.13; N,

EXAMPLE XLI 8 chloro 1,2,3,4 tetrahydro 2 methyl 10-pheny1- benzo[b][1,6]naphthyridin (5.0 g., 0.017 m.), 2.37 g. (0.017 In.) of 5,5-dimethyl-1,3-cyclohexanedione, 0.05 ml. of trifluoroacetic and ml. of benzene is refluxed for two hours over a Dean-Stark trap. The solution is evaporated and the residue crystallized from hot cyclohexane. Recrystallization from benzene affords 3-(8-chloro 1,2,3,4 tetrahydro 10 phenylbenzo [b] [1,6]naphthyridin-Z-yl)5,S-dimethyl-Z-cyclohexen-1-0ne as a crystalline solid, M.P. 114-150 C. (uncorr.).

Analysis.Calcd. for C H ClN O (percent): C, 74.88; H, 6.04; N, 6.73. Found (percent): C, 74.82; H, 6.00; N, 6.70.

23 EXAMPLE XLII A solution of 4.5 g. (0.0266 m.) of 2-amino-4,5-dimethoxybenzaldehyde, 3.0 g. (0.0266 m.) of 1-methyl-4- piperidone, 15 ml. of an aqueous 10 percent sodium hydroxide solution and 200 ml. of absolute ethanol is allowed to stir for six days at 25 C. the solution is filtered and hydrogen chloride gas and 500 ml. of diethyl ether are added. The hydroscopic salt is dissolved in Water, treated with charcoal, filtered and the filtrate made alkaline. The product is filtered, extracted with diethyl ether and recrystallized from water giving 1,2,3,4-tetrahydro-7,8-dimethoxy-lO-phenylbenzo[b] [1,6]naphthyridine as a crys talline solid.

EXAMPLE XLIII A solution of 7-chloro-l,2,3,4-tetrahydro-1,1,3,3-tetramethyl 10 (p methylthiophenyl)benzo[b] [1,6]naphthyridine (0.0156 m.) in glacial acetic acid (100 ml.) containing platinum oxide (0.3 g.) is hydrogenated at room temperature, and an initial hydrogen pressure of 46.5 p.s.i. for a period of twenty-four hours. The excess acetic acid is distilled in vacuo, the residue dissolved in water, and then basified whereupon the crude product separates. Recrystallization from cyclohexane-hexane affords 7-chloro 1,2,3,4,4a,5,10,10a octahydro 1,l,3,3 tetramethyl- 10- (p-methylthiophenyl) benzo [b] [1,6] naphthyridine.

When the above procedure is repeated employing the compounds of Examples XXXV-XLII, the following products are obtained:

10-(p-ethylthiophenyl) -1,2,3,4,4a,5,10,10a-ctahydro- 1,1,3,3-tetramethy1benzo [b] [l,6]naphthyridine;

10-(m-butylthiophenyl)-1,2,3 ,4,4a,5,10,10a-octahydro- 7-methylbenzo [b] 1,6] naphthyridine;

m- (7-chloro-1,2,3,4,4a,5 ,10,10a-octahydro-1, 1,3,3-tetramethylbenzo [b] [1,6] naphthyridin- 1 O-yl benzoic acid;

2-benzyl-7-chloro-1,2,3 ,4,4a,5, 10,1 Oa-octahydro-l 0- phenylbenzo [b] [1,6 naphthyridine;

8-chloro-1,2,3,4,4a,5,10,l0a-octahydro-1,1,2,3,3-pentamethyI-IO-phenylbenzo [b] [1,6 naphthyridine 1,2,3,4,4a,5,10,l0a-octahydro-Z-phenethyl-10-phenylbenzo [b] [1,6] naphthyridine;

2-benzyl-1,2,3,4,4a,5,10,10a-octahydro-lO-phenylbenzo [b] [1,6] naphthyridine;

3- 8-chloro-1,2,3 ,4,4a,5,10,IOa-octahydro-10-phenylbenzo [b] 1,6] naphthyridin-Z-yl) -5 ,5 -dimethylcyclohexan- 1-one and 1,2,3,4,4a,5,10, l0a-octahydro-7,8-dimethoxy-10- phenylbenzo [b] [1,6 [naphthyridine.

EXAMPLE XLIV A mixture of Z-aminobenzonitrile (5.00 g., 0.0423 m.) and 1-methyl-4-piperidone (4.80 g., 0.0423 In.) in polyphosphoric acid (105 g.) is gradually heated to 140- 150 C., and maintained at this temperature for one hour. The dark amber reaction mixture is poured with vigorous stirring into cold water (800 ml.). The resultant clear amber solution is decolorized, filtered through Celite, and the clear filtrate basified with 45 percent KOH (pH ca. An oil separates which slowly crystallizes. It is collected by filtration, washed with Water, air-dried; yield is 1.50 g. (16.7%) M.P. 82.5" C. (uncorr.). The filtrate is extracted with ether (6X 200 ml.) and the combined extracts successively washed with water, saturated salt solution, filtered through anhydrous sodium sulfate, and the filtrate concentrated in vacuo giving an oil which crystallizes on trituration with pentane; yield is 0.35 g. (3.9% M.P. 84 C. (uncorr.). Total yield of crude product is 1.85 g. (20.6%) which is directly converted to the dihydrochloride by saturating a tetrahydrofuran solution with dry hydrogen chloride; colorless crystals (1.90 g.) M.P. 301 C. dec. (uncorr.). Recrystallization of the crude dihydrochloride from 80% ethanol affords colorless crystals of the desired 10-arnino1,2,3,4-tetrahydro-2-methyl- 24 benzo [b] [l,6]naphthyridine dihydrochloride (1.10 g.) M.P. 321322 C. dec. (uncorr.).

Analysis.-Calcd. for C H Cl N (percent): C, 54.55; H, 5.85; Cl, 24.78; N, 14.68. Found (percent): C, 54.73; H, 5.85; Cl, 24.2; N, 14.79.

In a similar manner, 10-amino-2-ethyl-1,2,3,4-tetrahydro-8-methylbenzo[b] [1,6]naphthyridine and 10 amino- 1 benzyl 1,2,3,4 tetrahydro 2 methylbenzo[b] [1,6] naphthyridine are produced.

EXAMPLE XLV A mixture of Z-amino-4-chlorobenzonitrile (2.5 g.) and 1-benzyl-4-piperidone (2.5 g.) in trifluoroacetic acid g.) is gradually heated to reflux, and maintained at this temperature for one hour. The reaction mixture is then poured into cold water (500 ml.). The resultant solution is filtered, and the filtrate basified with 1 N solution hydroxide. The crude product is collected by filtration and Washed with water to yield the desired 10-amino-2-benzyl- 7 -chloro1,2,3,4-tetrahydrobenzo [b] [1,6] naphthyridine.

Dry hydrogen chloride is passed into an ether solution of the above prepared 10-amino-2-benzyl-7-chloro-1,2,3,4- tetrahydrobenzo[b] [1,6]naphthyridine. Thereafter, the resulting dihydrochloride salt is recrystallized from absolute ethanol to yield colorless crystals thereof.

EXAMPLE XLVI A mixture of 2-amino-3-chloro-benzonitrile (1.0 g.) and 1-phenethyl-4-piperidone (1.0 g.) in acetic acid (50.0 g.) is heated to reflux for sixteen hours. The reaction mixture is then poured into cold water (200 ml.). The resultant solution is filtered, and the filtrate basified with 1.5 N potassium hydroxide. The crude product is collected by filtration and washed with water to yield the desired 10 amino 6 chloro 1,2,3,4 tetrahydro 2- phenethylbenzo [b] 1,6 naphthyridine.

Similarly, 10-amino-2- (p-chlorophenyl) l ,2,3,4-tetrahydro-8-iodobenzo[b][1,6]naphthyridine and 10-an1ino-2- (p bromophenyl) 7-butyl-1,2,3,4-tetrahydrobenzo[b] [1,6]naphthyridine are synthesized.

EMMPLE XLVII A mixture of 2-amino-4-methylbenzonitrile (10.0 g.) and l-benzoyl-4-piperidone (10.0 g.) in benzenesulfonic acid (100 g.) is gradually heated to 100 C., and maintained at this temperature for one hour. The reaction mixture is then poured into cold Water (1500 ml.). The resultant solution is filtered, and the filtrate basified with 1.5 N sodium hydroxide. The crude product is collected by filtration and Washed with water to yield the desired 10-amino 2 benzoyl-1,2,3,4-tetrahydro-7-rnethylbenzo- [b] [1,6]naphthyridine.

Dry hydrogen chloride gas is passed into a tetrahydrofuran solution of the above prepared 10-amino-2-benzoyl- 1,2,3,4 tetrahydro 7 methylbenzo[b] [1,6]naphthyridine. The resulting salt is recrystallized from ethanol to yield a crystalling 10-amino-2-benzoyl-1,2,3,4-tetrahydro- 7-n1ethylbenzo [b] [1,6]naphthyridine dihydrochloride.

EXAMPLE XLVIII Additional benzo[b][1,6]naphthyridines having the formula:

*r a R2 25 are prepared according to the procedures of the above examples Where R, R R and R are defined as follows:

A mixture of 2-aminobenzonitrile (2.0 g.) and 2,2,6,6- tetramethyl-4-piperidone (2.0 g.) in polyphosphoric acid (75 g.) is gradually heated to 150 C., and maintained at this temperature for one and a half hours. The reaction mixture is then poured into cold water (400 ml.) The resultant solution is filtered, and the filtrate basified with 0.5 N sodium hydroxide. The crude product is collected by filtration and washed with water to yield the desired amino-Z-butyl-1,2,3,4-tetrahydro-1,1,3,3-tetramethylbenzo [b] 1,6] naphthyridine.

Similary, the

10-amino-Z-ethyl-1,2,3,4-tetrahydro-1,1,3,3-tetramethylbenzo[b] [1,6]naphthyridine and the 10-amino-1 ,2,3,4-tetrahydro-1, 1,3,3 -tetramethylbenzo- [b] [1,6] naphthyridine are prepared.

EXAMPLE L A mixture of Z-aminobenzonitrile (5.0 g.) and 1- ethylsulfouyl 4 piperidone (5.0 g.) in ethylsulfonic acid (150 g.) is gradually heated to 150 C., and maintained at this temperature for two hours. The reaction mixture is then poured into cold water (1200 ml.). The resultant solution is filtered, and the filtrate basified with 45% potassium hydroxide. The crude product is collected by filtration and Washed with Water to yield the desired 10-amino-2-ethylsulfonyl-1,2,3,4-tetrahydrobenzo [b] 1,6]naphthyridine.

The dihydrochloride of the above prepared IO-amino- 2 ethylsulfonyl 1,2,3,4 tetrahydrobenzo [b] [1,6]naphthyridine is prepared in accord with the procedure of Example XLIV.

EXAMPLE LI The following benzo [b] [1,6] naphthyridines having the formulae:

NH; R3 NH Biz amples, employing the appropriate Z-aminobenzonitrile and 4-piperidone compounds as starting materials:

10-amino-8-chloro-1,2,3,4-tetrahydro-l- (p-methoxyphenyl) -2-methylbenzo [b] 1,6] naphthyridine;

10-amino-8-chloro-1,2,3,4-tetrahydro-3-(p-methoxyphenyl) -2-methylbenzo [b] 1,6] naphthyridine 26 10-amino-1 ,2,3,4-tetrahydro-2-methoxyethyl-3 -phenethylbenzo [b] [1,6]naphthyridine; 1'0-amino-1 ,2,3,4-tetrahydro-2-methoxyethyl-l-phenethylbenzo [b] [1,6] naphthyridine; 10-amino-7-ethyl-1,2,3,4-tetrahydro-2-propionylbenzo [b] [1,6] naphthyridine; 10-amino-3-butyl-2-diethylcarbamoyl-1,2,3,4tetrahydrobenzo [b] [1,6] naphthyridine; IO-amino-1-butyl-2-diethylcarbamoyl-1,2,3,4-tetrahydrobenzo [b] 1,6] naphthyridine; 10-amino-1-butyl-2-diethylcarbamoyl-1,2,3 ,4-tetrahydro- [b] [1,6] naphthyridine; 10-amino-1- (p-bromophenyl)-1,2,3,4-tetrahydrobenzo- [b] [1,6] naphthyridne; and IO-amino- 1,2,3-4-tetrahydro-2- (p-tolyl benzo [b] [1,6]

naphthyridne EXAMPLE LII A mixture of 2-aminobenzonitrile (10.0 g.) and 2,6- dimethyl-4-piperidone (10.0 g.) in methylsulfonie acid g.) is gradually heated to C., and maintained at this temperature for two hours. The reaction mixture is then poured in cold water (2000 ml.). The resultant solution is filtered, and the filtrate basified with 1 N sodium hydroxide. The crude product is collected by filtration and washed with water to yield the desired 10-amino-1,2,3,4- tetrahydro- 1,3-dimethy1benzo [b] [1,6] naphthyridine.

Employing the above procedure the following compounds are also prepared:

10-amino-3- (p-chlorophenyl) -1,2,3,4-tetrahydro-2-propylbenzo [b] [1,6] naphthyridine;

10-arnino-1-( p-chlorophenyl 1 ,2,3,4-tetrahydro-2- propylbenzo[b] [1,6]naphthyridine;

10-aminol ,2,3,4-tetrahydro-2-methyl-3- (p-propylphenyl) benzo [b] 1,6] naphthyridine;

10-amino-1,2,3,4-tetrahydro-2-rnethyl-1-(p-propylphenyl) benzo [b] 1,6] naphthyridine; and

IO-amino-1,2,3,4-tetrahydro-8-iodo-2- (m-iodophenyl benzo [b] 1,6] naphthyridine EXAMPLE LIII A solution of 10-amino-l,2,3,4-tetrahydro-2-methylbenzo[b] [l,6]naphthyridine dihydrochloride, as prepared in Example XLIV, (0.0156 m.) in glacial acetic acid (100 ml.) containing platinum oxide (0.3 g.) is hydrogenated at room temperature, and an initial hydrogen pressure of 46.5 p.s.i. for a period of twenty-four hours. The excess actic acid is distilled in vacuo, the residue dissolved in water, and then basified whereupon the crude product separates. Recrystallization from cyclohexane-hexane aflords IO-amino-1,2,3,4,4a,5,10,10a-octahydro-2-methylbenzo [b] [1,6]naphthyridine.

When the above procedure is repeated for the 10- amino 1,2,3,4,4a,5,10,10a-octahydrobenzo[b] [1,6]naphthyridine of Example XLVLII, the corresponding 10- amino 1,2,3,4,4a,5,10,10a-octahydrobenzo [b] [1,6]naphthyridines are obtained.

EXAMPLE LIV 1-methyl-4-piperidone 66.0 g., 0.58 m.) is slowly added to a slurry of 4-chloroanthranilic acid (100.0 g., 0.58 m.) in phosphorous oxychloride (500 ml.) and the resulting mixture refluxed for two hours. The solvent is evaporated and the residue taken up in methylene chloride (2 liters). This is slowly added to a stirred ammonium hydroxide-ice solution (10 liters). The methylene chloride solution is Washed with water, dried over anhydrous sodium sulfate and evaporated giving 139.0 g. of a green solid. This solid is extracted with 1.5 l. of hexane, treated with charcoal, concentrated and crystallized giving 79.0 g. (49 percent) of crude product. Recrystallization from hexane gives 7,10 dichloro-1,2,3,4-tetrahydro-2-methylbenzo [b] [1,6]naphthyridine as a yellow crystalline solid, M.P. 114-5 C. (uncorn).

Analysis-Calcd. for C H CI N (percent): C, 58.46; H, 4.53; N, 10.49. Found (percent): C, 58.63; H, 4.28; N, 10.23.

The above prepared 7,10-dichloro-l,2,3,4-tetrahydro-2- methylbenzo[b][l,6]naphthyridine ,(5.0 g., 0.018 m.), and 3.36 g. (0.036 m.) of phenol are heated under nitrogen at 100 C. for fifteen minutes until a clear melt is obtained. Aniline (3.3 ml., 0.036 m.) is then added drop- Wise with stirring and the mixture is heated at 135140 C. for five hours. The reaction product is dissolved in methylene chlororide and extracted with a 20 percent potassium hydroxide solution. After being dried over anhydrous sodium sulfate, the methylene chloride solution is evaporated giving the free base. This product is triturated with ethyl acetate and recrystallized twice from acetonitrile giving 4.0 g. (69 percent) of 10-anilino-7- chloro 1,2,3,4 tetrahydro-Z-methylbenzo[b] [1,6]naphthyridine as a crystalline solid, M.P. 1978 C. (red melt) (uncorr.).

AnaIysis.-Calcd. for C H ClN (percent): C, 70.47; H, 5.60; N, 12.98. Found (percent): C, 70.40; H, 5.40; N, 12.72.

In a similar manner, the following compounds are prepared:

7,10-dichloro 1,2,3,4 tetrahydro-Z-methylbenzo[b] [1,6]naphthyridine (5.0 g., 0.018 m.) and phenol 3.38 g., 0.036 m.) are reacted to form the free base which is recrystallized three times from hexane to yield 7-chloro- 1,2,3,4-tetrahydro-2-methyl 10 phenoxybenzo[b] [1,6] naphthyridine as a crystalline solid, M.P. 1389 C. (uncorr.).

Analysis.--Calcd. for ClgHl'ZClNzO (percent): C, 70.25; H, 5.27; N, 8.64. Found (percent): C, 70.50; H, 4.91; N, 8.87.

7,10-dichloro 1,2,3,4 tetrahydro-2-methylbenzo[b] [1,6]naphthyridine (8.0 g., 0.03 m.), 5.65 g. (0.06 m.) of phenol and 7.0 g. (0.07 m.) of N-methylpiperazine are reacted to form the free base which is triturated with pentane and recrystallized from hexane giving 7-chloro- 1,2,3,4-tetrahydro-2-methyl-10-(4 methyl-l-piperazinyl) benzo[b][1,6]naphthyridine as a crystalline solid, M.P. 1145 C. (uncorr.)-

Analysis.-Calcd. for C H ClN (percent): C, 65.33; H, 7.02; N, 16.94. Found (percent): C, 65.74; H, 6.97; N, 16.79.

7,10-dichloro 1,2,3,4 tetrahydro-Z-methylbenzo[b] [1,6]naphthyridine (10.0 g., 0.0375 m.), 7.05 g. (0.075 m.) of phenol and 8.1 g. (0.075 m.) of o-phenylenediamine are reacted to form the free base which is triturated with carbon tetrachloride and recrystallized twice from methanol giving 10-(o-aminoanilino)-7-chloro 1,2,3,4- tetrahydro-Z-methylbenzo[b] [1,6]naphthyridine as a crystalline solid, M.P. 189192 C. (uncorr.).

Analysis.-Calcd. for C H ClN (percent): C, 67.35; H, 5.65; N, 16.54. Found (percent): C, 67.23; H, 5.79; N, 16.39.

When the above products are hydrogenated by the process of Example LIII, the following compounds are obtained:

10-anilino 7 chloro 1,2,3,4,4a,5,10a octahydro 2- methylbenzo [b] 1,6]naphthyridine;

7-chloro 1,2,3,4,4a,5,10,10a octahydro 2 methyl-10- phenoxybenzo [b] 1,6] naphthyridine;

7-chloro 1,2,3,4,4a,5,10,10a octahydro 2 methyl-10- (4 methyl 1 piperazinyl)benzo( [b] [1,6]naphthyridine; and

l-(o-aminoanilino) 7 chloro 1,2,3,4,4a,5,10,10a-octahydro-Z-methylbenzo [b] 1,6] naphthyridine EXAMPLE LV l-rnethyl 4 piperidone (130.0 g., 1.15 m.) S-chloro anthranilic acid (200.0 g., 1.16 m.) and phosphorous oxychloride (800 ml.) are allowed to react in a manner similar to Example LIV. The crude product is extracted several times with hot hexane. The combined extracts 28 are concentrated and the product allowed to crystallize giving g. (45%) of solid. Recrystallization of the crude product from hexane gives 8,l0-dichloro-l,2,3,4- tetrahydro-Z-methylbenzo[b] [1,6Jnaphthyridine as a crystalline solid, M.P. 889 C. (uncorr.).

Analysis.Calcd. for C H Cl N (percent): C, 58.46; H, 4.53; N, 10.49. Found (percent): C, 58.51; H, 4.31; N, 10.38.

The above prepared 8,10-dichloro-1,2,3,4-tetrahydro-2- methylbenzo[b][1,6]naphthyridine (5.0 g., 0.018 m.) and phenol (3.38 g., 0.036 m.) are reacted as described in the second paragraph of Example LIV to obtain the free 'base which is recrystallized three times from hexane to afford 8-chloro 1,2,3,4 tetrahydro-2-methyl-10-phenoxybenzo[ b][1,6]naphthyridine as a crystalline solid, M.P. 182-4 C. (uncorr.).

Analysis.Calcd. for C19H17C1N2O (percent): C, 70.25; H, 5.27; N, 8.64; Cl, 10.91. Found (percent): C, 70.39; H, 5.07; N, 8.77; Cl, 10.89.

In the same manner, the following compounds are prepared:

8,10dichloro 1,2,3,4 tetrahydro-Z-methylbenzo[b] [1,6]naphthyridine (15.0 g., 0.0562 m.), 10.6 g. (0.115 m.) of phenol and 10.3 ml. (0.115 m.) of aniline are reacted. Thereafter the reaction mixture is slurried with a mixture of 10% aqueous potassium hydroxide and diethyl ether. The insoluble product is filtered and recrystallized from acetonitrile giving 10-anilino-8-chloro 1,2, 3,4-tetrahydro-Z-methylbenzo [b] 1,6 naphthyridine as a crystalline solid (13.0 g., 72%), M.P. 1879 C. (red melt) (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 70.47; H, 5. 60; N, 12.98. Found (percent): C, 70.51; H, 5.40; N, 13.14.

8,10-dichloro 1,2,3,4 tetrahydro-Z-methylbenzo[b] [l,6]naphthyridine (8.0 g., 0.03 m.), 5.65 g. (0.06 In.) of phenol and 6.1 g. (0.06 m.) of dimethylaminopropylamine are reacted and the resulting free base is then recrystallized from cyclohexane followed by trituration with hexane to allord 8-chloro-1,2,3,4-tetrahydro-2-methyl-10- [(3 dimethylaminopropyl)amino]benzo[b][1,6]naphthyridine as a crystalline solid (5.0 g., 50%) M.P. 107- 8 C. (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 64.94; H, 7.57; N, 16.83. Found (percent): C, 65.23; H, 7.86; N, 16.84.

EXAMPLE LVI S-methoxyanthranilic acid (10.0 g., 0.0598 m.), 1- methyl-4-piperidone (13.5 g., 0.112 m.) and phosphorous oxychloride ml.) are allowed to react in a manner similar to Example LIV. The crude product is extracted several times with hot cyclohexane. The combined extracts are concentrated and the product allowed to crystallize. Rercrystallization of the crude product from the same solvent gives 10-chloro 1,2,3,4 tetrahydro-8-methoxy-2-methylbenzo[b] [1,6]naphthyridine (4.0 g., 25%), M.P. 126-7 C. (uncorr.).

Analysis.Calcd. for C H ClN O (percent): C, 64.00; H, 5.76; N, 10.66. Found (percent): C, 64.07; H, 5.46; N, 10.57.

When the above prepared naphthyridine is reacted with dimethylaminoet-hylamine by the procedure of the second paragraph of Example LIV, there is obtained 1,2,3,4- tetrahydro 8 methoxy-2-methyl-10-[(Z-dimethylaminoethyl) amino] benzo[b] [1,6]naphthyridine.

Similarly, the following products are obtained:

1,2,3,4-tetrahydro 8 methoxy-2-methy1-10-[ (4-dipropylaminobutyl amino] benzo [b] 1,6] naphthyridine;

10 (4-ethyl-1-piperazinyl) -1,2,3,4-tetrahydro-8-methoxy- Z-methylbenzo [b] 1,6] naphthyridine;

10 [(3 diethylaminopropyl)amino]-1,2,3,4-tetrahydro- 8-melhoxy-2-methylbenzo[b] [1,6]naphthyridine; and

10-(4-butyl-1-piperazinyl)-1,2,3,4-tetrahydro-8-methoxy- Z-methylbenzo [b] 1,6] naphthyridine 29 EXAMPLE LVlI -chloro-1,2,3,4-tetrahydro 2 methyl-8-nitrobenzo- [b][l,6]naphthyridine (5.0 g., 0.018 m.) and phenol (3.38 g., 0.036 m.) is heated under nitrogen at 100 C. for fifteen minutes until a clear melt is obtained. Morpholine (3.50 ml., 0.040 In.) is then added dropwise with stirring and the mixture is heated at 135-140 C. for five hours. The reaction product is dissolved in methylene chloride and extracted with a 20% potassium hydroxide solution. After being dried over anhydrous sodium sulfate, the methylene chloride solution is evaporated giving the free base. This product is triturated with ethyl acetate and recrystallized from benzene giving 1,2,3,4-tetrahydro- 2 methyl-IO-morpholino 8 nitrobenzo[b] [1,6]naphthyridine as a crystalline solid, M.P. 2167 C. (uncorr.).

Analysis.-Calcd. for C H N O (percent): C, 62.17; H, 6.14; N, 17.06. Found (percent): C, 61.99; H, 5.92; N, 16.98.

EXAMPLE LVIII A solution of 5.0 g. (0.018 m.) of 7,10-dichloro-1,2,3, 4 tetrahydro-Z-rnethylbenzo[b] [1,6]naphthyridine, 2.03 ml. (0.02 m.) of thiophenol, 1 ml. of concentrated hydrochloric acid and 300 ml. of 95 absolute ethanol is refluxed for four hours. After evaporation of the solution the residue is dissolved in methylene chloride and extracted with a 20% aqueous sodium carbonate solution. After being dried over anhydrous sodium sulfate the methylene chloride is evaporated and the residue is triturated with hexane. The crude product (5.2 g., 85%) is recrystallized twice from acetonitrile to give 7-ch1oro-1,2, 3,4-tetrahydro 2 methyl 10 phenthiobenzo [b] [1,6] naphthyridine, M.P. 131-2 C. (uncorr.).

Analysis.Calcd. for C H CIN S (percent): C, 66.94; H, 5.03; N, 8.22. Found (percent): C, 67.21; H, 4.73; N, 8.11.

EXAMPLE LlX A solution of 5.0 g. (0.0188 In.) of 8,10-dichloro-1,2, 3,4-tetrahydro-2-methylbenzo [b] [1,6]naphthyridine, 3.3 g. (0.0244 in.) of 3-aminopropanethiol hydrochloride, ml. of 18.5% aqueous potassium hydroxide (0.05 m.) and 30 ml. of absolute ethanol is refluxed for one and a half hours. After evaporation of the solution the residue is dissolved in methylene chloride and extracted with water. Evaporation of the methylene chloride solution gives the free base. Recrystallization of the product from hexane affords 10-(3-aminopropylthio)-8-chloro-1,2,3,4- tetrahydro 2 methylbenzo[b][1,6]naphthyridine as a crystalline solid (3.2 g., 53%), M.P. 8789 C. (uncorr.).

Analysis.Calcd. for C H ClN S (percent): C, 59.70; H, 6.26; N, 13.05; S, 9.96. Found (percent): C, 60.27; H, 6.40; N, 13.02; S, 9.95.

EXAMPLE LX A solution of 4.0 g. (0.015 m.) of 7,10-dichloro-1,2, 3,4-tetrahydro-Z-methylbenzo[b] [l,6]naphthyridine, 3.2 ml. (0.03 m.) of phenylhydrazine, 2.5 ml. of concentrated hydrochloric acid and 150 m1. of absolute ethanol is refluxed for six hours. After cooling the solution, a yellow solid is filtered which is then dissolved in methanol. To this solution is slowly added an aqueous sodium carbonate solution thereby effecting the precipitation of the free base. Two recrystallization of the product from benzene gives 1-(7-chloro 1,2,3,4 tetrahydro-Z-methylbenzo [b] [1,6]naphthyrin-10-yl) Z-phenylhydrazine as a crystalline solid, M.P. 1768 C. (decomp.) (uncorr.).

Analysis.Calcd. for C H ClN (percent): C, 67.35; H, 5.65; N, 16.54. Found (percent): C, 67.76; H, 5.43; N, 16.12.

EXAMPLE LXI A solution of 5.0 g. (0.0187 m.) of 8,10-dichloro 1,2, 3,4-tetrahydro-2-methylbenzo [b] 1,6] naphthyridine, 3 .5 g. (0.074 In.) of 95% hydrazine and 50 ml. of n-propyl alcohol is refluxed for four hours. The solution is evaporated and the residue treated simultaneously with methylene chloride and a sodium carbonate solution leaving an insoluble solid (2.0 g., 41%). Recrystallization of the product from benzene affords (8-chloro-1,2,3,4-tetrahydro-2-methylbenzo[b] [1,6]naphthyridin 10 yl)hydrazine as a crystalline solid, M.P. 172-3 C. (uncorr.).

Analysis.-Calcd. for C H ClN (percent): C, 59.44; H, 5.75; N, 21.33. Found (percent): C, 59.20; H, 5.66; N, 21.31.

' EXAMPLE LXII A solution of 8-chloro-1,2,3,4-tetrahydro-2-methyl-10- phenoxybenzo[b][1,6]naphthyridine (0.0312 In.) in glacial acetic acid (200 ml.) containing platinum oxide (0.6 g.) is hydrogenated at room temperature, and an initial hydrogen pressure of 46.5 p.s.i. for a period of twenty-four hours. The excess acetic acid is distilled in vacuo, the residue dissolved in water, and then basified whereupon the crude product separates. Recrystallization from cyclohexane-hexane affords 8-chloro-1,2,3,4,4a,5,10, l0a-octahydro 2-methyl-10-phenoxybenzo[b] [1,6]naphthyridine.

When the above procedure is repeated using the products of Examples LV-LXI as reactants, the following corresponding hydrogenated compounds are obtained:

10-anilino-8-chloro-1,2,3 ,4,4a,5,10,10a-octahydro-2- methylbenzo [b] 1,6] naphthyridine;

8-chloro-1,2,3 ,4,4a,5,10,10a-octahydro-2-methyl-10- [(3-dimethylarninopropyl amino] benzo [b] [1,6] naphthyridine;

1,2,3,4,4a,5,10,10a-octahydro-8-methoxy-2-methyl-10- [(2-dimethylaminoethyl amino] benzo [b] [1,6] naphthyridine;

1,2,3,4,4a,5,10,10a-octahydro-8-methoxy-2-methyl-10- [(4-dipropylaminobutyl) amino] benzo [b] [1,6] naphthyridine;

10-(4-ethyl-1-piperazinyl)-1,2,3,4,4a,5,10,10a-octahydro- 8-methoxy-2-methylzenzo [b] 1,6] naphthyridine;

10- (3-diethylaminopropyl amino] 1 ,2,3 ,4,4a,5,l0,10a-

octahydro-8-methoxy-2-methylbenzo [b] [1,6] naphthyridine;

10-(4-butyl-1-piperazinyl)-1,2,3,4,4a,5,10,10a-octahydro- 8-methoxy-2-methylbenzo[b] 1,6] naphthyridine;

8-amino-1,2,3 ,4,4a,5,10,10a-octahydro-2-methyl-10 morpholinobenzo[b] [1,6] naphthyridine;

7-chloro- 1,2,3 ,4,4a,5,10,l0a-octahydro-2-methyl-10- phenthiobenzo [b] 1,6] naphthyridine;

10- (3-aminopropylthio)-8-chloro-1,2,3 ,4,4a,5,10,10aoctahydro-Z-methylbenzo [b] 1,6] naphthyridine;

1-(7-chloro-1,2,3 ,4,4a,5,10,10a-octahydro-2-methylbenzo [b] 1,6] naphthyridin-10-yl)-2-phenyldrazine; and

(8-ch1oro-1,2,3 ,4,4a,5,10,10a-octahydro-Z-methylbenzo [b] 1,6] naphthyridin- 10-yl) hydrazine EXAMPLE LXIII An ethanolic solution of 2-benzyl-8-chloro-1,2,3,4-tetrahydro 10 phenylbenzo[b][l,6]naphthyridine hydrochloride (10.0 g., 0.0238 in.) is hydrogenated at three atmospheres of H pressure in the presence of a palladium catalyst, for thirty hours then at 60 C. for twenty hours. A total of 0.051 mole of hydrogen is consumed during this period. After separation of the catalyst by filtration, the solvent is distilled in vacuo and the solid residue recrystallized from absolute ethanol to yield colorless crystals of 1,2,3,4-tetrahydro-l0-phenylbenzo[b] [1,6]-naphthyridine dihydrochloride, M.P. 276.5-277 C. (uncorr.).

Analysis.Calcd. for C H CI N (percent): C, 64.85; H, 5.45; Cl, 21.29; N, 8.41. Found (percent): C, 64.58; H, 5.35; CI, 21.0; N, 8.18.

EXAMPLE LXIV The cti'rate salt of 8-chloro-1,2,3,4-tetrahydro-2-meth yl-10-phenylbenzo[b][1,6]naphthyridine is prepared by admixing an ethanolic solution of the compound with an aqueous solution containing two molar equivalents of citric acid and, thereafter, evaporating the co-solvents under vacuum.

Other acid addition salts of the 1,2,3,4-tetrahydrobenzonaphthyridine and 1,2,3,4,4a,5,10,10a-octahydrobenzonaphthyridine compounds described in the above examples are prepared by similar procedures employing hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, succinic acid, maleic acid and gluconic acid.

What is claimed is:

1. A compound selected from the group consisting of those having the formulae:

R3 R; R R

N-R; and N-RB N N R] R! I wherein R is hydrogen and R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is selected from the group consisting of hydrazino, amino, aminoanilino, anilino, di(lower)alkylamino(lower)alkylamino, amino(lower)alkylthio, phenyl, sulfamylphenyl, carboxyphenyl, phenylhydrazino, halophenyl, lower alkylphenyl, lower alkoxyphenyl, lower alkylthiophenyl, phenoxy, phenthio, morpholino, 2-pyridyl, Z-thienyl, Z-furyl and '4-(lower)alky1piperazino; R is selected from the group consisting of hydrogen, amidino, lower alkyl, di(lower)alkyl, phenyl, lower alkylphenyl, halophenyl, phen(lower)alkyl, benzoyl, lower alkanoyl, halo(lower)alkanoyl, dihalo(lower)alkanoyl, lower alkanoyloxy, di(lower)alkylamino (lower)alkanoyl, lower alkoxy(lower)alkyl, di(lower)alkylamino(lower) alkyl, dihydroxy(lower)alkyl and 5,5-dimethyl-3-oxo-1- cyclohexen-l-yl; and the pharmacologically acceptable acid addition salts thereof.

2. A compound as defined in claim 1, Formula I, which is: 8-chloro-1,2,3,4-tetrahydro 2 methyl-10-phenyl-1,3- ethanobenzo [b] [1,6] naphthyridine.

3. A pharmacologically acceptable acid addition salt of the compound defined in claim 2 in the form of the hydrochloride which is: 8-chloro-1,2,3,4-tetrahydro-2- methyl 10 phenyl-1,3-ethanobenzo[b][1,6]naphthyridine, monohydrochloride.

4. A process for the production of a compound having the formula:

NRa

N Br wherein R is hydrogen and R is selected from the group 32 consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is amino; R is selected from the group consisting of hydrogen, amidino, lower alkyl, di(lower)alkyl, phenyl, lower alkylphenyl, halophenyl, phen(lower)alkyl, benzoyl, lower alkanoyl, halo(lower)alkan0yl, dihalo (lower) alkanoyl, lower alkanoyloxy, di(lower)alkylamino(lower)alkanoyl, lower alkoxy (lower)alkyl, di (lower) alkylamino (lower) alkyl, dihydroxy (lower) alkyl and 5,5-dimethy1 3 oxo-l-cyclohexen-l-yl which comprises contacting a Z-aminobenzonitrile having the formula:

GEN

wherein R and R are as defined as above, with a 4- piperidone having the formula:

wherein R is defined as above, in the presence of a strong acid selected from the group of strong acids consisting of polyphosphoric, trifluoroacetic, acetic, benzenesulfonic, toluenesulfonic, methylsulfonic and ethylsulfonic ata temperature that is in the range from about C. to about 200 C. for a period of from about one-half hour to about two hours.

5. A process as described in claim 4 wherein the strong acid is polyphosphoric acid.

6. A process as described in claim 4 wherein the strong acid is polyphosphoric acid and the reaction is conducted at about C. for about one hour.

References Cited UNITED STATES PATENTS 3,225,055 12/1965 Lesher 260289X 3,324,135 6/1967 Lesher 260286X 3,375,253 3/1968 Fields et a1. 260286 OTHER REFERENCES Chem. Abstracts, vol. 60, C01. 8005-6 (1964). Kempter et al., Chem, Ber. vol. 98 (No. 2) pp. 419- 27 (1965).

DONALD G. DAUS, Primary Examiner US. Cl. XR 

